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Issue published April 15, 2026
Previous issue
Volume 136, Issue 8
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Review Series
Commentaries
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Research Articles
Corrigendum
On the cover:
Neuronal ERAD links ER proteostasis to neurometabolic dysfunction
Torres et al.
report that disruption of endoplasmic reticulum–associated degradation (ERAD) in neurons through conditional deletion of the ER membrane protein SEL1L impairs motor function and reduces survival in mice. The cover image shows immunofluorescence staining of the ER-resident chaperone marker KDEL (magenta) and the neuronal marker MAP2 (cyan) in a coronal brain section from a neuron-specific Sel1L-knockout mouse. Image credit: Mauricio Torres.
Review Series
Immune signaling and function in neurodegeneration
Yvonne L. Latour, Dorian B. McGavern
Yvonne L. Latour, Dorian B. McGavern
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Immune signaling and function in neurodegeneration
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Abstract
Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K–expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.
Authors
Yvonne L. Latour, Dorian B. McGavern
Commentaries
Diet’s rapid effects on the thyroid gland challenge unidirectional assumptions about hypothyroidism and energy balance
Arturo Hernandez, Francesco S. Celi
Arturo Hernandez, Francesco S. Celi
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Diet’s rapid effects on the thyroid gland challenge unidirectional assumptions about hypothyroidism and energy balance
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Abstract
Thyroid hormones provide crucial regulation of energy expenditure through their effects on thermogenesis, lipid metabolism, and mitochondrial function. Given their close relationship with overall metabolism, a deficit in thyroid hormones fittingly leads to a positive energy balance and weight gain. The direction of this process may also operate in reverse, according to recent research from Rampy et al. in this issue of JCI. These investigators found that mice introduced to a high-fat, high-sugar diet developed marked short-term intracellular stress and functional impairment in the thyroid gland, leading to alterations in serum thyroid hormone levels prior to measurable weight gain. This finding opens the possibility that thyroid dysfunction originates from persistent damage to the thyroid gland caused by sustained overnutrition.
Authors
Arturo Hernandez, Francesco S. Celi
Unconscious uncoupling: dysfunctional neurovascular responses to low glucose in type 1 diabetes and impaired hypoglycemia awareness
Stephanie A Amiel, Fernando O Zelaya
Stephanie A Amiel, Fernando O Zelaya
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Unconscious uncoupling: dysfunctional neurovascular responses to low glucose in type 1 diabetes and impaired hypoglycemia awareness
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Abstract
Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of severe hypoglycemia. A recent study by Filip et al. used MRI-based arterial spin labeling to compare regional cerebral blood flow (CBF) responses to experimental hypoglycemia across 3 groups: individuals without T1D and individuals with T1D, with or without IAH. All groups showed a CBF response to hypoglycemia in brain regions involved in learning and interoception, among others, but the responses were qualitatively different between groups and blunted in the presence of IAH. The association between the regional CBF and the hormonal responses to hypoglycemia was inverted in IAH, compared with that in individuals with preserved awareness. The findings add to work linking changes in cognitive processing to IAH development and its persistence in some individuals.
Authors
Stephanie A Amiel, Fernando O Zelaya
Gasdermin E: a missing link in muscle regeneration
Swathy Krishna, Jill A. Rafael-Fortney
Swathy Krishna, Jill A. Rafael-Fortney
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Gasdermin E: a missing link in muscle regeneration
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Abstract
Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.
Authors
Swathy Krishna, Jill A. Rafael-Fortney
Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation
Jessica A. Regan, Svati H. Shah
Jessica A. Regan, Svati H. Shah
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Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation
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Abstract
Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addressed the pathobiologic mechanisms of clonal hematopoiesis (CH), the age-related acquisition of expanded somatic clones in blood cells, as a potential driver of AAA. CH prevalence was high in patients being treated for AAA, and faster AAA expansion occurred over a period of one year in CH carriers. In an angiotensin II–induced model of AAA, mice carrying ten-eleven translocation 2 (Tet2) mutations (Tet2-CH) displayed accelerated AAA development and macrophage reprograming to an osteoclast-like state. Inhibition of this differentiation, targeting RANK/RANKL with FDA-approved therapies like alendronate and denosumab, suppressed aneurysmal growth. These findings suggest that macrophage-to-osteoclast differentiation may underlie the risk and progression of AAA associated with age-related CH, a mechanism that is modifiable through existing therapeutics.
Authors
Jessica A. Regan, Svati H. Shah
Research Letters
Sinus mast cell accumulation and persistence suggest a unique endotype in toxin exposure–associated chronic rhinosinusitis
Xinyu Wang, Yung-An Huang, Anshika Sethi, Christopher Yue, Sydney Brack, Aiswarya Chattuparambil Binoy, Lauren Crowther, Carol Yan, Adam Deconde, Anton Kushnaryov, Andrew Vahabzadeh-Hagh, Jacob Husseman, Maia Little, Allyssa Strohm, Lily Jih, Jonathan J. Lyons, David H. Broide, Taylor A. Doherty
Xinyu Wang, Yung-An Huang, Anshika Sethi, Christopher Yue, Sydney Brack, Aiswarya Chattuparambil Binoy, Lauren Crowther, Carol Yan, Adam Deconde, Anton Kushnaryov, Andrew Vahabzadeh-Hagh, Jacob Husseman, Maia Little, Allyssa Strohm, Lily Jih, Jonathan J. Lyons, David H. Broide, Taylor A. Doherty
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Sinus mast cell accumulation and persistence suggest a unique endotype in toxin exposure–associated chronic rhinosinusitis
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Abstract
Authors
Xinyu Wang, Yung-An Huang, Anshika Sethi, Christopher Yue, Sydney Brack, Aiswarya Chattuparambil Binoy, Lauren Crowther, Carol Yan, Adam Deconde, Anton Kushnaryov, Andrew Vahabzadeh-Hagh, Jacob Husseman, Maia Little, Allyssa Strohm, Lily Jih, Jonathan J. Lyons, David H. Broide, Taylor A. Doherty
Characterization of elite controllers with an undetectable intact HIV DNA reservoir
Jana Blazkova, Brooke D. Kennedy, Jesse S. Justement, Victoria Shi, Adeline Sewack, Maegan R. Manning, Sonali Dasari, Kathleen Gittens, Susan Moir, Mark Connors, Stephen A. Migueles, Tae-Wook Chun
Jana Blazkova, Brooke D. Kennedy, Jesse S. Justement, Victoria Shi, Adeline Sewack, Maegan R. Manning, Sonali Dasari, Kathleen Gittens, Susan Moir, Mark Connors, Stephen A. Migueles, Tae-Wook Chun
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Characterization of elite controllers with an undetectable intact HIV DNA reservoir
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Abstract
Authors
Jana Blazkova, Brooke D. Kennedy, Jesse S. Justement, Victoria Shi, Adeline Sewack, Maegan R. Manning, Sonali Dasari, Kathleen Gittens, Susan Moir, Mark Connors, Stephen A. Migueles, Tae-Wook Chun
Research Articles
Inhibiting LSD1 unlocks retinoid AP-1 programming to activate epithelial immunity and skin tumor suppression
Nina Kuprasertkul, Alyssa F. Moore, Carina A. D’souza, Julia Chini, Eun-Kyung Ko, Sijia Huang, Shuo Zhang, Ashley S. Anderson, Shaun Egolf, Laura V. Pinheiro, Alison Jaccard, Claudia T. Magahis, Lydia Bao, Yann Aubert, Cyria Olingou, Stephen M. Prouty, Donna Brennan-Crispi, David A. Hill, John T. Seykora, Kathryn E. Wellen, Brian C. Capell
Nina Kuprasertkul, Alyssa F. Moore, Carina A. D’souza, Julia Chini, Eun-Kyung Ko, Sijia Huang, Shuo Zhang, Ashley S. Anderson, Shaun Egolf, Laura V. Pinheiro, Alison Jaccard, Claudia T. Magahis, Lydia Bao, Yann Aubert, Cyria Olingou, Stephen M. Prouty, Donna Brennan-Crispi, David A. Hill, John T. Seykora, Kathryn E. Wellen, Brian C. Capell
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Inhibiting LSD1 unlocks retinoid AP-1 programming to activate epithelial immunity and skin tumor suppression
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Abstract
Lysine-specific demethylase 1 (LSD1; KDM1A) orchestrates context-dependent chromatin programs, yet its role in epithelial immunity remains largely unknown. Here, we identify LSD1 as a central brake on retinoid-driven and activator protein-1–driven (AP-1–driven) enhancer activation in epidermis and demonstrate that its inhibition induces antitumor immunity. Whereas epidermal LSD1 is required during development, acute loss or topical inhibition in adult skin was tolerated and triggered coordinated expression of retinoic acid signaling, lipid remodeling, and chemokine induction pathways. CUT&RUN profiling revealed that LSD1 occupies enhancer regions enriched for AP-1 motifs at retinoid metabolism, lipid homeostasis, and immune genes. LSD1 loss increased H3K4me1/2 and gene activation at these sites, licensing a poised AP-1–retinoid program. Single-cell spatial analyses showed that discrete keratinocyte subsets initiate retinoid signaling to recruit dendritic cells and activate CD4+ T cell responses. Topical LSD1 inhibition suppressed cutaneous squamous cell carcinoma in 2 models while amplifying keratinocyte–immune cell crosstalk. Functional perturbations revealed that retinoid signaling partially contributes to, whereas CD4+ T cells are essential for, tumor control. These findings define LSD1 as a master repressor of epithelial immune competence and nominate LSD1 inhibition as a therapeutic strategy to activate retinoid–AP-1 enhancer circuits and drive CD4-dependent tumor immunity in skin cancer.
Authors
Nina Kuprasertkul, Alyssa F. Moore, Carina A. D’souza, Julia Chini, Eun-Kyung Ko, Sijia Huang, Shuo Zhang, Ashley S. Anderson, Shaun Egolf, Laura V. Pinheiro, Alison Jaccard, Claudia T. Magahis, Lydia Bao, Yann Aubert, Cyria Olingou, Stephen M. Prouty, Donna Brennan-Crispi, David A. Hill, John T. Seykora, Kathryn E. Wellen, Brian C. Capell
Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
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Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance
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Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.
Authors
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
Postnatal
Slc26a4
gene therapy improves hearing and structural integrity in a hereditary hearing loss model
Yi-Hsiu Tsai, Peng-Yu Wu, Yu-Chi Chuang, Chun-Ying Huang, Hiroki Takeda, Hiroshi Hibino, Chen-Chi Wu, Yen-Fu Cheng
Yi-Hsiu Tsai, Peng-Yu Wu, Yu-Chi Chuang, Chun-Ying Huang, Hiroki Takeda, Hiroshi Hibino, Chen-Chi Wu, Yen-Fu Cheng
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Postnatal
Slc26a4
gene therapy improves hearing and structural integrity in a hereditary hearing loss model
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Abstract
Mutations in SLC26A4 are the second most common cause of hereditary hearing loss (HL) in many Asian countries, leading to DFNB4, a condition characterized by progressive HL and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored because of the lack of suitable animal models and the challenges of prenatal intervention. To our knowledge, this study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4-mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.
Authors
Yi-Hsiu Tsai, Peng-Yu Wu, Yu-Chi Chuang, Chun-Ying Huang, Hiroki Takeda, Hiroshi Hibino, Chen-Chi Wu, Yen-Fu Cheng
Galectin-3 mediates lysosome-related inflammation within monocyte-derived macrophages in a mouse model of ischemic brain injury
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
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Galectin-3 mediates lysosome-related inflammation within monocyte-derived macrophages in a mouse model of ischemic brain injury
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Abstract
Circulating monocyte-derived macrophages (MDMø) rapidly invade the brain after stroke, exerting both detrimental and beneficial effects. Elucidating mechanisms that mediate detrimental properties of MDMø may identify therapeutic strategies to divert MDMø from destructive phenotypes, while preserving their favorable effects. Toward this goal, the current study explores the function of Galectin-3 (GAL3) in MDMø and elucidates mechanisms whereby MDMø-derived GAL3 exacerbates stroke injury. In the acutely injured brain, GAL3 expression was upregulated primarily within MDMø. Global KO of GAL3 reduced brain infarcts in the short term but did not sustain long-term positive outcomes. Using BM chimera mice, macrophage transplantation, and myeloid cell–specific GAL3-KO (LysMCre+/–Lgals3fl/fl) mice, we demonstrated that GAL3 in MDMø mediated acute infarct expansion after stroke. Coculturing brain lysate–treated, BM-derived macrophages (BMDMs) with oxygen glucose deprivation–challenged neurons induced neurotoxicity that was mitigated by the cell-permeable, selective GAL3 inhibitor TD139. GAL3 triggered cathepsin induction and lysosomal leakage in BMDMs, leading to inflammasome activation. Systemic and transient TD139 treatment in the acute injury phase reduced infarcts, tempered neuroinflammation, and improved long-term neurological outcomes. Therefore, MDMø-derived GAL3 represents a drug target that could be accessed in peripheral blood to potentially mitigate post-stroke brain injury.
Authors
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
Overnutrition in mice impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
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Overnutrition in mice impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations
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Abstract
Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt — but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.
Authors
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
Distinct neuronal alterations distinguish two subtypes of sporadic Creutzfeldt-Jakob disease with shared dysfunctional pathways
Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Arielle Hay, Ryan O. Walters, Tina Thomas, Gianluigi Zanusso, James A. Carroll, Cathryn L. Haigh
Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Arielle Hay, Ryan O. Walters, Tina Thomas, Gianluigi Zanusso, James A. Carroll, Cathryn L. Haigh
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Distinct neuronal alterations distinguish two subtypes of sporadic Creutzfeldt-Jakob disease with shared dysfunctional pathways
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Prion diseases are a family of transmissible, neurodegenerative conditions caused by misfolded proteins called prions. Human cerebral organoids can be infected with prions from sporadic Creutzfeldt-Jakob Disease (sCJD) brain tissue. Initial experiments indicated that the cerebral organoids may be able to differentiate biological properties of different sCJD subtypes. If so, it would be possible to investigate the pathogenic similarities and differences. Herein, we investigated multiple infections of cerebral organoids with 2 sCJD subtypes, comparing hallmark features of disease as well as neuronal function and health. Our results show that, while all infections produced seeding-capable prion protein (PrP), which increased from 90–180 days after infection, a sCJD subtype preference for protease-resistant PrP deposition was observed. Both subtypes caused substantial electrophysiological dysfunction in the infected organoids, which appeared uncoupled from PrP deposition. Neuronal dysfunction was associated with changes in neurotransmitter receptors that differed between the subtypes but produced the same outcome of a shift from inhibitory toward excitatory neurotransmission. Further changes indicated shared deficits in mitochondrial dynamics, and subtype influenced alterations in intracellular signaling pathways, cytoskeletal structure, and the extracellular matrix. We conclude that cerebral organoids demonstrate both common mitochondrial deficits and sCJD subtype–specific changes in neurotransmission and organoid architecture.
Authors
Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Arielle Hay, Ryan O. Walters, Tina Thomas, Gianluigi Zanusso, James A. Carroll, Cathryn L. Haigh
Distinct HIF1
and HIF2
functions control skeletal muscle metabolism and erythropoiesis
Junhyeong Lee, Merc Emil Matienzo, Sangyi Lim, Edzel Evallo, Yeongsin Kim, Sujin Jang, Keon Kim, Chang Hyeon Choi, Youn Ho Han, Chang-Min Lee, Tae-Il Jeon, Sang-Ik Park, Jun Wu, Dong-il Kim, Min-Jung Park
Junhyeong Lee, Merc Emil Matienzo, Sangyi Lim, Edzel Evallo, Yeongsin Kim, Sujin Jang, Keon Kim, Chang Hyeon Choi, Youn Ho Han, Chang-Min Lee, Tae-Il Jeon, Sang-Ik Park, Jun Wu, Dong-il Kim, Min-Jung Park
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Distinct HIF1
and HIF2
functions control skeletal muscle metabolism and erythropoiesis
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Abstract
Skeletal muscle frequently encounters hypoxic stress, particularly during exercise, but the specific functions of the hypoxia-inducible factors HIF1α and HIF2α within myofibers remain unclear due to the lack of appropriate in vivo models. Here, we generated 3 complementary mouse models, myofiber-specific triple-PHD knockout (PHD mTKO) and inducible myofiber-specific overexpression of stabilized HIF1α or HIF2α, to delineate isoform-specific roles of HIFα signaling in skeletal muscle. HIF1α stabilization increased the proportion of oxidative fibers yet paradoxically impaired exercise capacity and mitochondrial function. In contrast, HIF2α activation protected against diet-induced obesity, improved glucose tolerance, and maintained mitochondrial function without altering fiber-type composition. Notably, HIF2α stabilization markedly elevated erythropoietin (EPO) expression in skeletal muscle and serum. Myofiber-specific deletion of EPO in the PHD mTKO background abolished polycythemia, demonstrating that this phenotype is driven specifically by muscle-derived EPO. Together, these findings uncover distinct roles of HIF1α and HIF2α in regulating muscle metabolism and mitochondrial function and establish the PHD–HIF2α axis as a myofiber-derived driver of systemic EPO production.
Authors
Junhyeong Lee, Merc Emil Matienzo, Sangyi Lim, Edzel Evallo, Yeongsin Kim, Sujin Jang, Keon Kim, Chang Hyeon Choi, Youn Ho Han, Chang-Min Lee, Tae-Il Jeon, Sang-Ik Park, Jun Wu, Dong-il Kim, Min-Jung Park
Colonic
Engyodontium
fungus triggers neutrophil antimicrobial activity to suppress
Lactobacillus johnsonii
–derived glutamic acid–maintained Tregs
Xinying Wang, Haiyang Sun, Ying Tan, Shaoting Xu, Zishan Liu, Kaile Ji, Ding Qiu, Jianping Deng, Bingbing Feng, Xueting Wu, Yoichiro Iwakura, Minhu Chen, Rui Feng, Chanyan Huang, Ce Tang
Xinying Wang, Haiyang Sun, Ying Tan, Shaoting Xu, Zishan Liu, Kaile Ji, Ding Qiu, Jianping Deng, Bingbing Feng, Xueting Wu, Yoichiro Iwakura, Minhu Chen, Rui Feng, Chanyan Huang, Ce Tang
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Colonic
Engyodontium
fungus triggers neutrophil antimicrobial activity to suppress
Lactobacillus johnsonii
–derived glutamic acid–maintained Tregs
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Abstract
Isolating commensal fungi from mouse intestines has been challenging, limiting our understanding of their role in intestinal immune homeostasis and diseases. Using an Fc fusion protein of the C-type lectin receptor Dectin-2, we successfully purified the commensal Ascomycota fungus Engyodontium sp. from mouse feces. Engyodontium enhances the antimicrobial activity of colonic neutrophils via the CARD9 pathway and exacerbates colitis by impairing the colonization of intestinal Lactobacillus johnsonii WXY strain. L. johnsonii produces high levels of l-glutamic acid by expressing the glutaminase-encoding gene glsA to facilitate Treg expansion via enhancing IL-2 receptor signaling. Patients with Crohn disease (CD) and ulcerative colitis harbored increased Engyodontium and decreased L. johnsonii abundance. Engyodontium directly induced calprotectin in human colonic neutrophils, and patients with CD had lower levels of l-glutamic acid, which also promoted human Treg expansion. These findings highlight the Engyodontium-calprotectin axis against the Lactobacillus-glutamate-Treg cascade to aggravate colitis, suggesting commensal Engyodontium-triggered signaling as a therapeutic target for mucosal inflammatory diseases.
Authors
Xinying Wang, Haiyang Sun, Ying Tan, Shaoting Xu, Zishan Liu, Kaile Ji, Ding Qiu, Jianping Deng, Bingbing Feng, Xueting Wu, Yoichiro Iwakura, Minhu Chen, Rui Feng, Chanyan Huang, Ce Tang
Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice
Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang L. Lin, Jiwon Hwang, Xinxin Chen, Alan C. Rupp, Abigail J. Tomlinson, Andrew J. Scott, Zhen Zhao, Daniel R. Wahl, Martin G. Myers Jr., Costas A. Lyssiotis, Ling Qi
Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang L. Lin, Jiwon Hwang, Xinxin Chen, Alan C. Rupp, Abigail J. Tomlinson, Andrew J. Scott, Zhen Zhao, Daniel R. Wahl, Martin G. Myers Jr., Costas A. Lyssiotis, Ling Qi
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Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice
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Abstract
Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age — mirroring core clinical features observed in affected patients — despite preserved neuronal numbers and only modest ER stress. Multiomics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulting from induction of the integrated stress response. Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing insight into the molecular basis of ERAD-related neurodevelopmental disease.
Authors
Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang L. Lin, Jiwon Hwang, Xinxin Chen, Alan C. Rupp, Abigail J. Tomlinson, Andrew J. Scott, Zhen Zhao, Daniel R. Wahl, Martin G. Myers Jr., Costas A. Lyssiotis, Ling Qi
Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
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Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders
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Abstract
Alternative splicing–triggered nonsense-mediated mRNA decay (AS-NMD) critically regulates gene expression, but the extent to which neuronal genes are regulated by AS-NMD remains understudied. Here, we identified over 3,000 developmentally regulated AS-NMD exons in mouse and human brains and validated them in cultured neurons. AS-NMD suppresses synaptic genes during brain development and differentially regulates more than 200 causal genes for neurodevelopmental disorders (NDDs). We detected a poison exon in GRIA2 and identified splice-switching antisense oligonucleotides that suppressed GRIA2 NMD and increased its functional isoforms. In summary, this study uncovers genes repressed by AS-NMD in the brain and nominates amenable splice-switching targets for treating dominant NDDs such as autism spectrum disorders and developmental epileptic encephalopathy.
Authors
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
AAV-mediated gene therapy in a model of SLC13A5 citrate transporter disorder rescues epileptic and metabolic phenotypes
Lauren E. Bailey, Raegan M. Adams, Morgan K. Schackmuth, Irvin T. Garza, Krishanna Knight, Sydni K. Holmes, Meghan M. Eller, MinJae Lee, Rachel M. Bailey
Lauren E. Bailey, Raegan M. Adams, Morgan K. Schackmuth, Irvin T. Garza, Krishanna Knight, Sydni K. Holmes, Meghan M. Eller, MinJae Lee, Rachel M. Bailey
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AAV-mediated gene therapy in a model of SLC13A5 citrate transporter disorder rescues epileptic and metabolic phenotypes
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Abstract
SLC13A5 citrate transporter disorder is a rare epileptic encephalopathy caused by loss-of-function pathogenic variants in the SLC13A5 gene. Loss of sodium/citrate cotransporter (NaCT) function causes a severe early-life epilepsy resulting in lifelong developmental disabilities and increased extracellular citrate. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and neurodevelopmental SLC13A5 phenotype. We performed preclinical studies in SLC13A5-deficient (KO) mice evaluating phenotype rescue with adeno-associated virus (AAV) vector carrying a functional copy of the human SLC13A5 gene (AAV9/SLC13A5). Cerebrospinal fluid delivery of AAV9/SLC13A5 decreased extracellular citrate levels, normalized electrophysiologic and sleep architecture abnormalities, and restored resistance to chemically induced seizures and death. Treatment benefits were achieved with administration during early brain development and in young adult mice, indicating therapeutic efficacy across developmental and postdevelopmental stages. Comparison of delivery routes in young adult KO mice showed that higher brain targeting achieved with intra–cisterna magna delivery resulted in greater treatment benefit as compared with intrathecal lumbar puncture delivery. Together, these results support further development of AAV9/SLC13A5 for treating SLC13A5 citrate transporter disorder.
Authors
Lauren E. Bailey, Raegan M. Adams, Morgan K. Schackmuth, Irvin T. Garza, Krishanna Knight, Sydni K. Holmes, Meghan M. Eller, MinJae Lee, Rachel M. Bailey
Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
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Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis
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Abstract
Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction–associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.
Authors
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
Peripheral vaccination-induced brain-resident memory CD8
T cells durably protect mice against intracranial malignancy
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
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Peripheral vaccination-induced brain-resident memory CD8
T cells durably protect mice against intracranial malignancy
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Abstract
Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.
Authors
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
RNA-binding protein LARP6 coordinates hepatic stellate cell activation and liver fibrosis
Hyun Young Kim, Orel Mizrahi, Wonseok Lee, Sara B. Rosenthal, Cuijuan Han, Brian A. Yee, Steven M. Blue, Jesiel Diaz, Jyotiprakash P. Jonnalagadda, Lena A. Street, Kanani Hokutan, Haeum Jang, Charlene Miciano, Chen-Ting Ma, Andrey A. Bobkov, Eduard Sergienko, Michael R. Jackson, Marko Jovanovic, Branko Stefanovic, Tatiana Kisseleva, Gene W. Yeo, David A. Brenner
Hyun Young Kim, Orel Mizrahi, Wonseok Lee, Sara B. Rosenthal, Cuijuan Han, Brian A. Yee, Steven M. Blue, Jesiel Diaz, Jyotiprakash P. Jonnalagadda, Lena A. Street, Kanani Hokutan, Haeum Jang, Charlene Miciano, Chen-Ting Ma, Andrey A. Bobkov, Eduard Sergienko, Michael R. Jackson, Marko Jovanovic, Branko Stefanovic, Tatiana Kisseleva, Gene W. Yeo, David A. Brenner
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RNA-binding protein LARP6 coordinates hepatic stellate cell activation and liver fibrosis
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Abstract
Metabolic syndrome and excessive alcohol consumption (MetALD) result in liver injury and fibrosis, which are driven by increased collagen production by activated hepatic stellate cells (HSCs). Our previous studies demonstrated that LARP6, an RNA-binding protein, may facilitate collagen production. However, the expression and function of LARP6 as a regulator of fibrosis development in a disease-relevant model remain poorly understood. We demonstrated that LARP6 was upregulated in human activated HSCs in metabolic dysfunction–associated steatohepatitis (MASH) and MetALD. By using single-nucleus RNA-seq and assay for transposase-accessible chromatin sequencing, we showed that JUNB upregulated LARP6 expression in activated HSCs. Moreover, LARP6 knockdown in human HSCs suppressed fibrogenic gene expression. By integrating enhanced crosslinking and IP analysis and ribosome profiling in HSCs, we showed that LARP6 interacted with mature mRNAs comprising more than 300 genes, including RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. IP–mass spectrometry analysis demonstrated LARP6 protein–protein interactions with mRNA translation components and the actin cytoskeleton. Furthermore, Dicer substrate siRNA-based HSC-specific gene knockdown or pharmacological inhibition of LARP6 attenuated fibrosis development in human MASH and MetALD liver spheroids. Our results suggest LARP6 plays a key role in fibrogenic gene regulation and that targeting LARP6 in human HSCs may represent a therapeutic approach for liver fibrosis.
Authors
Hyun Young Kim, Orel Mizrahi, Wonseok Lee, Sara B. Rosenthal, Cuijuan Han, Brian A. Yee, Steven M. Blue, Jesiel Diaz, Jyotiprakash P. Jonnalagadda, Lena A. Street, Kanani Hokutan, Haeum Jang, Charlene Miciano, Chen-Ting Ma, Andrey A. Bobkov, Eduard Sergienko, Michael R. Jackson, Marko Jovanovic, Branko Stefanovic, Tatiana Kisseleva, Gene W. Yeo, David A. Brenner
GSDME–IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
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GSDME–IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration
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Abstract
Metabolic–inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in postsurgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and scRNA-seq analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism to lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols (TAGs) and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitor (FAP) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1+Cd163+Txnip+ tissue-resident macrophages (TRMs), as validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable with those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function and curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME–IL-18–TRM axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.
Authors
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast–like differentiation
Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara
Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara
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Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast–like differentiation
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Abstract
Aortic aneurysms are age-linked aortic dilations that progress silently and carry high mortality rates following rupture. Immune cells are recognized drivers of aneurysm pathogenesis. Clonal hematopoiesis is an age-related expansion of somatically mutated hematopoietic stem cells that reshapes immune function and contributes to diverse age-associated diseases. However, its contribution to aneurysm pathogenesis remains unclear. In this study, targeted ultradeep sequencing of patient specimens revealed a high prevalence of clonal hematopoiesis–associated mutations that correlated with faster aneurysm expansion. Thus, we modeled clonal hematopoiesis by competitively transplanting ten-eleven translocation 2–deficient (Tet2-deficient) bone marrow into apoliprotein E–KO (Apoe-KO) mice and induced aneurysms with angiotensin II. Mice with Tet2 clonal hematopoiesis developed significantly greater aortic dilation than did controls. Interestingly, Tet2-deficient macrophages adopted an acid phosphatase 5, tartrate resistant (ACP5+), osteoclast-like state and produced more matrix metalloproteinase 9 (MMP9). Both genetic and pharmacological inhibition of osteoclast-like differentiation suppressed the Tet2-mediated aneurysmal growth in vivo. Thus, Tet2-driven clonal hematopoiesis accelerated aortic aneurysm progression through MMP9-producing, osteoclast-like macrophages and therefore represents a tractable therapeutic axis.
Authors
Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara
4 Integrin blockade impairs CD8
T cell neuroimmune surveillance following SIV infection
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
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4 Integrin blockade impairs CD8
T cell neuroimmune surveillance following SIV infection
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Abstract
Integrin-targeted therapies are under investigation for HIV-associated neuroinflammation, yet their effect on CNS antiviral immunity remains undefined. We examined the role of α4 integrin in T cell–mediated neuroimmune surveillance using SIV-infected macaques with α4 blockade and T cell–specific α4-deficient mice. In macaques, α4 blockade preserved CD4+ Th1 cell access to the brain parenchyma but impaired CD8 effector recruitment, disrupting antiviral control. Despite stable cerebrospinal fluid viral loads, hippocampal SIV RNA increased under blockade. Single-cell analyses revealed α4 enrichment in CD8 effector memory (Tem) cells; blockade reduced inferred CD8+ Tem-monocyte interactions and heightened innate immune activation in the hippocampus. Microscopy demonstrated persistent SIV-induced microglial simplification despite treatment. Th1 CD4 effectors correlated positively with gray matter viral RNA, whereas α4β7+ CD8+ T cells correlated inversely, implicating impaired CD8+ Tem recruitment in elevated parenchymal viral burden. In mice, α4 proved dispensable for CD4 trafficking to inflamed brain but essential for CD8 effector access across CNS compartments and for both subsets to reach skull marrow. These findings establish that α4 integrin governs CD8-mediated neuroimmune surveillance through coordinated cellular positioning, with blockade enabling viral seeding while disrupting spatially organized antiviral defense.
Authors
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
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Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer
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Abstract
Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes — proinflammatory and proresolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution macrophages through phagocytosis/efferocytosis, ω-3 fatty acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty acid pathways. Knocking down ELOVL5 — an elongase involved in ω-3 and ω-6 metabolism — mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.
Authors
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
Biallelic
GLTP
mutations cause nonsyndromic epidermal differentiation disorder via disrupted epidermal glucosylceramide transport
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
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Biallelic
GLTP
mutations cause nonsyndromic epidermal differentiation disorder via disrupted epidermal glucosylceramide transport
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Abstract
Ceramides are essential skin lipids for maintaining the mammalian skin permeability barrier, which protects against external stimuli. The precursor of epidermal ceramides, glucosylceramides (GlcCer), is synthesized within granular keratinocytes while its precise cellular transport mechanisms remain poorly characterized. Here, we identified 3 pathogenic variants in the GLTP gene, which encodes glycolipid transfer protein, in 5 unrelated families with nonsyndromic epidermal differentiation disorder presenting with generalized skin scaling. The biallelic GLTP variants resulted in loss of competent GLTP expression. CRISPR/Cas9-generated Gltp-knockout mice exhibited lethal barrier defects, partially recapitulating the clinical features of our patients. We demonstrated that GLTP facilitated GlcCer transport in differentiated keratinocytes, with its deficiency causing impaired GlcCer trafficking and consequent aberrant retention in lysosomes, thereby disrupting lysosome function. The lysosomal dysfunction impaired autophagy flux, resulting in delayed keratinocyte terminal differentiation, which is expected to compromise the skin barrier integrity and ultimately lead to abnormal scaling. Pharmacological inhibition of GlcCer synthesis effectively rescued both autophagy and keratinocyte differentiation defects. Our findings establish GLTP as a novel underlying gene for nonsyndromic epidermal differentiation disorders and unravel its essential role in maintaining skin homeostasis during terminal differentiation by mediating epidermal GlcCer transport.
Authors
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
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Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance
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Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPis) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naive, high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-Seq, and multiplex immunohistochemistry to identify 2 therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell–enriched niche that expands in resistant lesions and a niche enriched in tumor-associated macrophage (TAM) that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell–derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer–associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs. 76.2%; P = 0.021) and shorter progression-free survival (median 13.5 vs. 28.3 months; P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity—effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN-SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.
Authors
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
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Clinical Research and Public Health
Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia
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Abstract
BACKGROUND Recurrent hypoglycemia in type 1 diabetes (T1D) may culminate in impaired awareness of hypoglycemia (IAH). While neuroimaging studies identified affected brain regions, more complex perspectives integrating vascular dynamics with endocrine profile are needed.METHODS Here, 26 healthy adults, 30 T1D patients with normal hypoglycemia awareness (NAH), and 25 T1D patients with IAH underwent a hyperinsulinemic stepped clamp (euglycemia → hypoglycemia 50 mg/dL) combined with pseudo-continuous arterial spin-labeling MRI. Cerebral blood flow (CBF) and sympathetic vasomotor range (0.02–0.05 Hz) CBF oscillations were modeled against serially sampled plasma cortisol, epinephrine, norepinephrine, and glucagon.RESULTS In healthy individuals treated as controls, hypoglycemia evoked robust thalamo-striatal and salience–interoceptive CBF increases (mean Cohen’s d across significant clusters = 0.93) and suppression of vasomotor oscillations (d = 0.71). T1D retained CBF response but failed to attenuate oscillations (dT1D>controls = 0.43). IAH further blunted hypoglycemia-associated CBF increase, especially in thalamus, striatum, and insula (dNAH>IAH = 0.51). Hormone-CBF coupling differed quantitatively: cortisol/epinephrine–CBF correlations were positive in controls (r = 0.37/0.26), negative in NAH (–0.16/–0.40), and strongly positive in IAH (0.42/0.46).CONCLUSION Thus, our findings indicate that T1D disrupts dynamic, sympathetic modulation of CBF, whereas IAH additionally impairs perfusion reserve and shows maladaptive catecholamine-dependent CBF regulation, suggesting a qualitatively distinct neurovascular phenotype.TRIAL REGISTRATION ClinicalTrials.gov: NCT02747680 and NCT02866435.FUNDING NIH (P41-EB-015894, P30-NS-076408, R01-DK-099137, R56-DK-099137, and DP1 AG093028); National Center for Advancing Translational Sciences of the NIH (KL2-TR-000113 and UL1-TR-000114); DP1 AG093028; Charles University, Czech Republic (Cooperatio Program, research area NEUR), Brain Dynamics (grant number CZ.02.01.01/00/22_008/0004643); General University Hospital in Prague (MH CZ-DRO-VFN64165).
Authors
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
CD38 expression by neonatal human naive CD4
T cells shapes their distinct metabolic and tolerogenic properties
Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt
Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt
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CD38 expression by neonatal human naive CD4
T cells shapes their distinct metabolic and tolerogenic properties
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Abstract
Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naive CD4+ T cells into Tregs. We demonstrated heightened capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4+ T cells. Further, this was linked to a distinct cord blood metabolic profile and elevated neonatal expression of the NADase, CD38. Early-life naive CD4+ T cells demonstrated a metabolic preference for glycolysis, which directly facilitated their differentiation trajectory. We revealed an age-dependent gradient in CD38 levels on naive CD4+ T cells and showed that high CD38 expression contributes to the glycolytic state and tolerogenic potential of neonatal CD4+ T cells, effects mediated at least partly via the NAD-dependent deacetylase SIRT1. Thus, the early-life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naive CD4+ compartment.
Authors
Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt
Carriage of rare
APOB
variants predisposes to severe steatotic liver disease and hepatocellular carcinoma
Matteo Mureddu, Serena Pelusi, Oveis Jamialahmadi, Marijana Vujkovic, Lorenzo Miano, Hadi Eidgah Torghabehei, Luisa Ronzoni, Francesco Malvestiti, Marco Saracino, Giulia Periti, Vittoria Moretti, Craig C. Teerlink, Julie A. Lynch, Philip S. Tsao, Josephine P. Johnson, Vincenzo La Mura, Robertino Dilena, Saleh A. Alqahtani, Alessandro Cherubini, EPIDEMIC Study Investigators, Million Veteran Program, Francesco Paolo Russo, Roberta D’Ambrosio, Mirella Fraquelli, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Elisabetta Bugianesi, Rosellina M. Mancina, Paolo Parini, Daniele Prati, Kyong-Mi Chang, Carolin V. Schneider, Stefano Romeo, Luca VC Valenti
Matteo Mureddu, Serena Pelusi, Oveis Jamialahmadi, Marijana Vujkovic, Lorenzo Miano, Hadi Eidgah Torghabehei, Luisa Ronzoni, Francesco Malvestiti, Marco Saracino, Giulia Periti, Vittoria Moretti, Craig C. Teerlink, Julie A. Lynch, Philip S. Tsao, Josephine P. Johnson, Vincenzo La Mura, Robertino Dilena, Saleh A. Alqahtani, Alessandro Cherubini, EPIDEMIC Study Investigators, Million Veteran Program, Francesco Paolo Russo, Roberta D’Ambrosio, Mirella Fraquelli, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Elisabetta Bugianesi, Rosellina M. Mancina, Paolo Parini, Daniele Prati, Kyong-Mi Chang, Carolin V. Schneider, Stefano Romeo, Luca VC Valenti
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Clinical Research and Public Health
Carriage of rare
APOB
variants predisposes to severe steatotic liver disease and hepatocellular carcinoma
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Abstract
BACKGROUND Metabolic dysfunction–associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODS We investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTS In the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7–70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33–2.49 and 3.53, 95% CI: 2.09–5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONS Rare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDING European Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH.
Authors
Matteo Mureddu, Serena Pelusi, Oveis Jamialahmadi, Marijana Vujkovic, Lorenzo Miano, Hadi Eidgah Torghabehei, Luisa Ronzoni, Francesco Malvestiti, Marco Saracino, Giulia Periti, Vittoria Moretti, Craig C. Teerlink, Julie A. Lynch, Philip S. Tsao, Josephine P. Johnson, Vincenzo La Mura, Robertino Dilena, Saleh A. Alqahtani, Alessandro Cherubini, EPIDEMIC Study Investigators, Million Veteran Program, Francesco Paolo Russo, Roberta D’Ambrosio, Mirella Fraquelli, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Elisabetta Bugianesi, Rosellina M. Mancina, Paolo Parini, Daniele Prati, Kyong-Mi Chang, Carolin V. Schneider, Stefano Romeo, Luca VC Valenti
Corrigendum
Corrigendum to Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
Karl Bacos, Alexander Perfilyev, Alexandros Karagiannopoulos, Elaine Cowan, Jones K. Ofori, Ludivine Bertonnier-Brouty, Tina Rönn, Andreas Lindqvist, Cheng Luan, Sabrina Ruhrmann, Mtakai Ngara, Åsa Nilsson, Sevda Gheibi, Claire L. Lyons, Jens O. Lagerstedt, Mohammad Barghouth, Jonathan L.S. Esguerra, Petr Volkov, Malin Fex, Hindrik Mulder, Nils Wierup, Ulrika Krus, Isabella Artner, Lena Eliasson, Rashmi B. Prasad, Luis Rodrigo Cataldo, Charlotte Ling
Karl Bacos, Alexander Perfilyev, Alexandros Karagiannopoulos, Elaine Cowan, Jones K. Ofori, Ludivine Bertonnier-Brouty, Tina Rönn, Andreas Lindqvist, Cheng Luan, Sabrina Ruhrmann, Mtakai Ngara, Åsa Nilsson, Sevda Gheibi, Claire L. Lyons, Jens O. Lagerstedt, Mohammad Barghouth, Jonathan L.S. Esguerra, Petr Volkov, Malin Fex, Hindrik Mulder, Nils Wierup, Ulrika Krus, Isabella Artner, Lena Eliasson, Rashmi B. Prasad, Luis Rodrigo Cataldo, Charlotte Ling
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Amended Article
Corrigendum to Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
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Abstract
Authors
Karl Bacos, Alexander Perfilyev, Alexandros Karagiannopoulos, Elaine Cowan, Jones K. Ofori, Ludivine Bertonnier-Brouty, Tina Rönn, Andreas Lindqvist, Cheng Luan, Sabrina Ruhrmann, Mtakai Ngara, Åsa Nilsson, Sevda Gheibi, Claire L. Lyons, Jens O. Lagerstedt, Mohammad Barghouth, Jonathan L.S. Esguerra, Petr Volkov, Malin Fex, Hindrik Mulder, Nils Wierup, Ulrika Krus, Isabella Artner, Lena Eliasson, Rashmi B. Prasad, Luis Rodrigo Cataldo, Charlotte Ling
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Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy
Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) or nephrotic syndrome type 14 (NPHS14), is an autosomal recessive multisystem disorder caused by loss-of-function mutations in...
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Genetics
Metabolism
Nephrology
Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy
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Abstract
Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) or nephrotic syndrome type 14 (NPHS14), is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency using patient fibroblasts, SGPL1-knockout HEK293T cells, and Sgpl1–/– and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labelling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (i) feedback regulation of de novo sphingolipid synthesis via the ORMDL–ceramide axis and (ii) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis — either by exogenous sphingolipid load or disruption of compensatory regulation — induces pathological intracellular S1P accumulation. In vivo, Sgpl1–/– mice exhibited pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho–ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with Fasudil mitigated renal cytoskeletal defects in Sgpl1–/– and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho–ROCK hyperactivation as a tractable therapeutic target in SPLIS.
Authors
Adam Majcher, Ranjha Khan, Kathrin Buder, Florence Bourquin, Julie D. Saba, Thorsten Hornemann
T cell receptor signaling induces expression of lysine demethylase KDM6B to maintain Treg homeostasis
Regulatory T (Treg) cells expressing Forkhead Box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a Histone H3 lysine 27 (H3K27) methyltransferase, is...
Research
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Immunology
Pulmonology
T cell receptor signaling induces expression of lysine demethylase KDM6B to maintain Treg homeostasis
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Abstract
Regulatory T (Treg) cells expressing Forkhead Box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a Histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg cell identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, was also required for Treg cell identity and function after activation. Treg-specific deletion of Kdm6b impaired tissue Treg cell fate and function. KDM6B was upregulated following T cell antigen receptor (TCR) signaling in Treg cells and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at cis-regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.
Authors
Minghong He, Beisi Xu, Pria G. Bose, Morgan J. McCullough, Rani S. Sellers, Xinying Zong, Wenjie Qi, Brianna L. Banten, Miriya K. Tune, Matthew P. Zimmerman, Genevieve N. Mullins, Brian C. Miller, J. Justin Milner, Jason K. Whitmire, Ageliki Tsagaratou, Karl B. Shpargel, Claire M. Doerschuk, Yong-Dong Wang, Jacob A. Steele, Shondra M. Pruett-Miller, Yongqiang Feng, Jason R. Mock
The N-terminus of Apolipoprotein B mediates the interaction of atherogenic lipoproteins with endothelial cells
Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and...
Research
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Metabolism
Vascular biology
The N-terminus of Apolipoprotein B mediates the interaction of atherogenic lipoproteins with endothelial cells
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Abstract
Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.
Authors
Ainara G. Cabodevilla, Camila Calistru, Waqas Younis, Dimitris Nasias, Tse W.W. Ho, Narasimha Anaganti, Swati Valmiki, Sujith Rajan, Jana Gjini, Rufina Kore, Carmen Hannemann, Nicholas O. Davidson, Tomas Vaisar, Jenny E. Kanter, Karin E. Bornfeldt, Edward A. Fisher, Warren L. Lee, Tobias Madl, M. Mahmood Hussain, Ira J. Goldberg
Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis
Typ515 (W515) mutations in the protein MPL are one of key driver mutations promoting BCR/ABL-negative myeloproliferative neoplasms (MPNs), but their effects on hematopoietic stem cells (HSCs) and...
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Hematology
Oncology
Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis
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Abstract
Typ515 (W515) mutations in the protein MPL are one of key driver mutations promoting BCR/ABL-negative myeloproliferative neoplasms (MPNs), but their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia (ET)-like MPN phenotypes, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically we observed that MplW514L-conditioned HSC compartment had a unique disease-initiating capacity however it did not exhibit a obvious advantage of competitive repopulation over wild-type control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of MPLW515L mutation in HSCs, and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.
Authors
Shujing Zhang, Jingjing Liu, yuan li, Yi Wang, Lingling Wang, Miaomiao Xu, Yanxia Li, Ge Dong, Shanshan Wang, Yanmei Li, Zhigang Cai, Baobing Zhao
DYRK1A enhances antitumor immunity in type 1 conventional dendritic cells via mTORC1 activation
Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly...
Research
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Cell biology
Immunology
DYRK1A enhances antitumor immunity in type 1 conventional dendritic cells via mTORC1 activation
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Abstract
Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responded to TLR and growth factor stimulation and acted as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impaired antitumor immunity and accelerated tumor progression in murine models. Mechanistically, DYRK1A mediated the phosphorylation of the mTORC1 inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting the mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restored their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlated with effector T-cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A-TSC2-mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.
Authors
Hongjiao Wang, He Jiang, Songlin He, Songwen Ren, Haiwen Li, Wangnan Liu, Chunyun Zhou, Pan Zhu, Keren Chen, Weijia Cao, Yan Qin, Dan Du, Nengming Xiao, Hongling Huang, Chun-Jung Ko, Yiming Zheng, Bo Wang, Qiang Zou, Jian-Hong Shi, Xun Li, Zuliang Jie
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