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Issue published April 22, 2026
Volume 11, Issue 8
Previous Issue
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Research Letter
Research Articles
Corrigendum
Spatial proteomic mapping of the human and mouse retina using IBEX
Meng et al.
report a spatial proteomic atlas of the mouse and human retina as a resource for studying the cellular landscape of the eye in health and disease. The cover image shows a confocal micrograph of a healthy human retina using IBEX highly multiplexed immunohistochemistry. Image credit: Colin J. Chu.
Research Letter
A single dose of i.v. iron induces cardiac ferroptosis in murine cardiometabolic heart failure
Caitlin M. Pavelec, Leigh A. Bradley, Priyanka Rawat, Luke S. Dunaway, Maya Bolger-Chen, Bethany A. Gholson, Jonathan R. Lindner, Brant E. Isakson, Norbert Leitinger, Matthew J. Wolf
Caitlin M. Pavelec, Leigh A. Bradley, Priyanka Rawat, Luke S. Dunaway, Maya Bolger-Chen, Bethany A. Gholson, Jonathan R. Lindner, Brant E. Isakson, Norbert Leitinger, Matthew J. Wolf
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A single dose of i.v. iron induces cardiac ferroptosis in murine cardiometabolic heart failure
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Abstract
Authors
Caitlin M. Pavelec, Leigh A. Bradley, Priyanka Rawat, Luke S. Dunaway, Maya Bolger-Chen, Bethany A. Gholson, Jonathan R. Lindner, Brant E. Isakson, Norbert Leitinger, Matthew J. Wolf
Research Articles
Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra
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Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis
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Abstract
Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.
Authors
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra
FOSL2
regulates endothelial cell state and chromatin accessibility in systemic sclerosis pulmonary vascular remodeling
Rithika Behera, Yuechen Zhou, Peter H. Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M. Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y. Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis
Rithika Behera, Yuechen Zhou, Peter H. Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M. Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y. Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis
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FOSL2
regulates endothelial cell state and chromatin accessibility in systemic sclerosis pulmonary vascular remodeling
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Abstract
Systemic sclerosis (SSc) is characterized by fibrosis and vasculopathy affecting the skin and internal organs, leading to multiorgan dysfunction. Injury of microvascular endothelial cells (ECs) in SSc impairs blood flow and causes tissue ischemia, leading to vascular complications such as Raynaud’s, digital ulcers, and pulmonary hypertension (PH). PH in SSc presents as group 1 pulmonary arterial hypertension or as group 3 PH related to hypoxia and interstitial lung disease (ILD), both major causes of mortality. Analysis of multiome data from SSc ILD-PH lungs inferred transcription factors regulating EC phenotype, including FOSL2. Overexpression of FOSL2 in transgenic mice (Fosl2tg) leads to vascular changes mirroring human SSc-PH, such as intimal thickening and fibrosis. scRNA-Seq analysis of altered EC gene expression in Fosl2tg mice showed strong overlap with altered EC gene expression in SSc-ILD-PH. Overlapping as well as discrete EC gene expression in Sugen/hypoxia- and hypoxia-treated mice suggested that FOSL2 regulates both hypoxia-dependent and -independent pathways in Fosl2tg mice and SSc-ILD-PH. A deep learning model, ChromBPNet, inferred increased AP-1 binding at base pair resolution in SSc-ILD-PH ECs, and binding to the same motifs was found upon FOSL2 overexpression in primary vascular ECs, highlighting FOSL2’s key role in driving the pathological changes seen in SSc-ILD-PH.
Authors
Rithika Behera, Yuechen Zhou, Peter H. Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M. Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y. Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis
Loss of fungal sensing exacerbates liver injury in a murine model of MASLD
Vijay Pandyarajan, So Yeon Kim, Takashi Tsuchiya, Selena Liu, Sadam H. Bhat, Jieun Kim, David M. Underhill, Mazen Noureddin, Shelly C. Lu, Ekihiro Seki
Vijay Pandyarajan, So Yeon Kim, Takashi Tsuchiya, Selena Liu, Sadam H. Bhat, Jieun Kim, David M. Underhill, Mazen Noureddin, Shelly C. Lu, Ekihiro Seki
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Loss of fungal sensing exacerbates liver injury in a murine model of MASLD
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Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a global health concern with limited interventions. While the role of gut bacteria in MASLD has been extensively studied, the contribution of gut fungi remains largely unexplored. This study investigates the impact of fungal dysbiosis and the role of CARD9, a key adaptor protein in fungal sensing on gut-liver axis dysfunction in MASLD. Patients with advanced liver fibrosis exhibited distinct mycobiota profiles. Using a Card9-deficient mouse model subjected to high-fat, high-glucose/-fructose feeding, we observed exacerbated liver injury and fibrosis accompanied by fungal dysbiosis, paralleling our findings in human patients. Beyond its established expression in myeloid cells, CARD9 was also detected in intestinal enterocytes where its expression was diminished under metabolic stress. Intestinal organoids with CARD9 inhibition had reduced expression of antimicrobial Reg3g, the tight junction protein ZO-1, and the antifungal enteroendocrine hormone PYY. These findings suggest that CARD9 maintains gut barrier integrity, preventing microbial translocation and subsequent liver injury and fibrosis. Our results provide insights into the interplay between fungal dysbiosis, gut barrier dysfunction, and MASLD, and identify CARD9 as a key protein within this axis.
Authors
Vijay Pandyarajan, So Yeon Kim, Takashi Tsuchiya, Selena Liu, Sadam H. Bhat, Jieun Kim, David M. Underhill, Mazen Noureddin, Shelly C. Lu, Ekihiro Seki
Inherited human CARD9 deficiency impairs lymphoid cell, but not fibroblast, IL-17–mediated immunity
Erika Della Mina, Carlos G. El-Haddad, Timothy A. West, Clara W.T. Chung, Jing Jing Li, Vivienne Lea, Elissa K. Deenick, Filomeen Haerynck, Jean-Laurent Casanova, Anne Puel, Cindy S. Ma, Stuart G. Tangye, Alisa Kane
Erika Della Mina, Carlos G. El-Haddad, Timothy A. West, Clara W.T. Chung, Jing Jing Li, Vivienne Lea, Elissa K. Deenick, Filomeen Haerynck, Jean-Laurent Casanova, Anne Puel, Cindy S. Ma, Stuart G. Tangye, Alisa Kane
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Inherited human CARD9 deficiency impairs lymphoid cell, but not fibroblast, IL-17–mediated immunity
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Abstract
Nearly 100 individuals have been identified who carry deleterious biallelic germline variants in CARD9 and experience life-threatening, invasive fungal infections caused by Ascomycetes but are otherwise resistant to other infectious agents. CARD9 is an adaptor protein expressed predominantly in myeloid cells, which functions downstream of dectin receptors, pattern recognition receptors for fungal antigens, to activate innate immune responses. The impact of CARD9 deficiency on lymphocytes, however, is less clear. We deciphered the functional consequences and delineated mechanisms of disease in a patient (P1) with a nonsense germline homozygous CARD9 variant (c.673A>T/p.K225*) and invasive Candida disease. P1’s PBMCs expressed truncated CARD9 and showed significantly reduced cytokine production in response to fungal ligands. P1 had reduced frequencies of circulating memory CD4+ TH17-like (CCR6+CXCR3–) cells. In addition, in vitro differentiation of P1’s naive CD4+ T cells into IL-17A/IL-17F–secreting cells was greatly impaired. Consistent with impaired responses of innate and adaptive immune cells from P1 in vitro, proportions of Candida-specific CD4+ T cells were strongly and selectively diminished. Our findings suggest that the CARD9 variant identified in P1 is pathogenic, affecting not only CARD9-induced immunity mediated by myeloid cells but also CD4+ T cell–intrinsic IL-17–dependent immunity and Candida-specific T cell responses.
Authors
Erika Della Mina, Carlos G. El-Haddad, Timothy A. West, Clara W.T. Chung, Jing Jing Li, Vivienne Lea, Elissa K. Deenick, Filomeen Haerynck, Jean-Laurent Casanova, Anne Puel, Cindy S. Ma, Stuart G. Tangye, Alisa Kane
Hydrogen sulfide alleviates hyperoxia effects on mitochondria in human developing airway smooth muscle
Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick
Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick
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Hydrogen sulfide alleviates hyperoxia effects on mitochondria in human developing airway smooth muscle
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Abstract
Moderate hyperoxia (30%–60% O2) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via airway smooth muscle (ASM), a key regulator of bronchoconstriction, bronchodilation, and remodeling. Understanding how O2 exposure drives long-term bronchial changes in prematurity is critical for developing therapies for airway disease across the lifespan. Premature lungs have immature antioxidant defenses, potentially due to disrupted mitochondrial dynamics, increasing susceptibility to O2-induced oxidative stress. Thus, mitochondrial homeostasis is highly relevant to ASM dysfunction and airway disease. We propose that hyperoxia in prematurity promotes mitochondrial dysfunction, and that the gasotransmitter hydrogen sulfide (H2S) mitigates O2-induced mitochondrial damage in developing ASM. Human fetal ASM (fASM) cells were exposed to moderate hyperoxia to investigate the effects of exogenous H2S donors (GYY4137, AP39) and stabilization of cystathionine β-synthase (CBS), an H2S biosynthetic enzyme, on mitochondrial structure and function. Hyperoxia impaired fASM cell mitochondrial integrity, while H2S donors in particular, or CBS stabilization attenuated adverse O2 effects on mitochondrial morphology, ROS, respiration, calcium regulation, and contractility. These findings highlight the therapeutic potential of H2S in the premature lung exposed to moderate hyperoxia.
Authors
Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick
Bone morphogenetic proteins 4 and 7 increase human white and brown adipocyte thermogenic capacity
Kelly T. Long, Cheryl Cero, Sahara L. Ali, Nhuquynh Nguyen, Adrienne R. Guarnieri, Ju Hee Kim, Young Jae Bahn, Jurgen Heymann, Jonathan M. Dreyfuss, Sushil G. Rane, Yu-Hua Tseng, Aaron M. Cypess
Kelly T. Long, Cheryl Cero, Sahara L. Ali, Nhuquynh Nguyen, Adrienne R. Guarnieri, Ju Hee Kim, Young Jae Bahn, Jurgen Heymann, Jonathan M. Dreyfuss, Sushil G. Rane, Yu-Hua Tseng, Aaron M. Cypess
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Bone morphogenetic proteins 4 and 7 increase human white and brown adipocyte thermogenic capacity
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Abstract
Adipocytes exist along a functional spectrum: white adipocytes are energy storing, and brown adipocytes have thermogenic capacity such that activation may counteract obesity-related disease. In between are UCP1-expressing beige adipocytes, which can transition between these two energetic states. We previously showed that bone morphogenetic protein 7 (BMP7), a member of the TGF-β superfamily, enables differentiation of brown preadipocytes to mature thermogenic cells. To see whether immortalized, clonal human white and brown preadipocytes (hWAs and hBAs, respectively) would become more thermogenic in response to BMP exposure, we treated them with BMP7 or BMP4 for the first 7 days of a 30-day differentiation protocol. In hBAs, absence of either BMP7 or BMP4 led to lower expression of brown-specific markers and oxygen consumption relative to 7 days with either BMP. hWAs treated for 7 days with either BMP did not increase expression of thermogenic protein UCP1 nor induce a brown-like transcription profile. However, BMP-treated hWAs produced adipocytes that had higher basal and drug-induced maximal oxygen consumption, which was UCP1-independent and due substantially to the futile creatine cycle. Our results demonstrate that energetically quiescent hWAs can be pushed into an energy-expending phenotype without transdifferentiation into beige adipocytes, providing a new approach to treat obesity-related metabolic disease.
Authors
Kelly T. Long, Cheryl Cero, Sahara L. Ali, Nhuquynh Nguyen, Adrienne R. Guarnieri, Ju Hee Kim, Young Jae Bahn, Jurgen Heymann, Jonathan M. Dreyfuss, Sushil G. Rane, Yu-Hua Tseng, Aaron M. Cypess
Macrophage ferritin heavy chain/
-synuclein regulatory axis modulates ferroptosis during kidney injury
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary E. Miller, Bronte Johnson, Yanfeng Zhang, Laura A. Volpicelli-Daley, Lauren A. Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, Jozsef Balla, Christian Faul, Abolfazl Zarjou
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary E. Miller, Bronte Johnson, Yanfeng Zhang, Laura A. Volpicelli-Daley, Lauren A. Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, Jozsef Balla, Christian Faul, Abolfazl Zarjou
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Macrophage ferritin heavy chain/
-synuclein regulatory axis modulates ferroptosis during kidney injury
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Abstract
Macrophages, endowed with remarkable phenotypic plasticity, are essential for orchestrating injury responses and regulating iron homeostasis. Given the central role of ferritin heavy chain (FtH) as a molecular rheostat linking iron sequestration to redox-dependent signaling, we examined how myeloid FtH governs renal iron trafficking and ensuing oxidative stress pathways during acute kidney injury (AKI). Transcriptome analysis revealed coupling of FtH deficiency in monocytes and macrophages with activation of ferroptosis, a regulated cell death associated with iron accumulation. Moreover, myeloid FtH deletion worsened AKI, increasing leukocyte infiltration and iron deposition, together with ferroptosis-associated gene induction, oxidative stress, and lipid peroxidation. Notably, α-synuclein (SNCA), an iron-binding protein and the main pathological driver of Parkinson’s disease, was robustly induced both by FtH deficiency and following AKI. Mechanistic studies showed that monomeric SNCA exhibits ferrireductase activity, amplifying redox cycling and promoting ferroptotic cell death. Furthermore, SNCA expression was elevated in kidney pathologies characterized by leukocyte expansion in both mouse models and human cohorts, suggesting that inflammatory microenvironments promote SNCA accumulation and redox imbalance. These findings define a macrophage FtH/SNCA regulatory axis as a key driver of ferroptosis in AKI, implicating SNCA as a pathological nexus between iron dyshomeostasis and inflammatory kidney injury.
Authors
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary E. Miller, Bronte Johnson, Yanfeng Zhang, Laura A. Volpicelli-Daley, Lauren A. Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, Jozsef Balla, Christian Faul, Abolfazl Zarjou
High tumor mutational burden and
PIK3CA
mutations correlate with poor Merkel cell carcinoma–specific survival
Matheus Lobo, Furkan Bahar, Julia L. Schnabel, Joao P. Duprat Neto, Aniket Shetty, Karam Khaddour, Manisha Thakuria, Ann W. Silk, James A. DeCaprio
Matheus Lobo, Furkan Bahar, Julia L. Schnabel, Joao P. Duprat Neto, Aniket Shetty, Karam Khaddour, Manisha Thakuria, Ann W. Silk, James A. DeCaprio
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High tumor mutational burden and
PIK3CA
mutations correlate with poor Merkel cell carcinoma–specific survival
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Abstract
Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04–25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10–3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.
Authors
Matheus Lobo, Furkan Bahar, Julia L. Schnabel, Joao P. Duprat Neto, Aniket Shetty, Karam Khaddour, Manisha Thakuria, Ann W. Silk, James A. DeCaprio
Epithelial SLPI expression in severe inflammatory bowel disease relates to high IL-17 and neutrophil programming
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
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Epithelial SLPI expression in severe inflammatory bowel disease relates to high IL-17 and neutrophil programming
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Abstract
Heterogeneity in disease severity and treatment response in inflammatory bowel disease (IBD) likely evolves from individual differences in host-microbiota-immune interactions. Histological evaluation of intestinal biopsies is central to diagnosis, but histological parameters that define underlying immune mechanisms are limited. We investigated histological features that distinguish individual patient immune profiles in therapy-naive pediatric IBD patients (age 6–18 years) using biopsy immunohistochemistry and transcriptomics and plasma proteomics across two cohorts. High colonic epithelial expression of secretory leukocyte protease inhibitor (SLPI), a microbiota-induced regulator of epithelial function, occurred in IBD patients with high clinical disease activity and more severe endoscopic and microscopic disease activity. SLPI expression was related to increased neutrophil infiltration, transcriptomic signatures of activation, and genes known to associate with therapeutic resistance. High SLPI colocalized with high densities of IL-17–secreting cells and was associated with high plasma concentrations of Th17-related immune proteins. Additionally, patients with high intestinal SLPI had an intrinsically different immunotype, in which circulating neutrophils exhibited altered transcription of genes involved in neutrophil granule formation, phagocytosis, oxidative phosphorylation, and interferon signaling. Thus, high colonic SLPI expression at diagnosis associates with severe IBD, increased IL-17A–neutrophil pathway responses, and altered transcriptomic wiring of circulating neutrophils.
Authors
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
A stromal platform for robust expansion of functional IL-10–producing B cells for immune regulation
Ryo Kawakami, Keisuke Imabayashi, Akemi Baba, Yuichi Saito, Kazuhiko Kawata, Yutaro Yada, Airi Shibata, Rinka Ito, Ryo Kurasawa, Ryota Higuchi, Sungyeon Park, Hiroaki Niiro, Shinya Tanaka, Yoshihiro Baba
Ryo Kawakami, Keisuke Imabayashi, Akemi Baba, Yuichi Saito, Kazuhiko Kawata, Yutaro Yada, Airi Shibata, Rinka Ito, Ryo Kurasawa, Ryota Higuchi, Sungyeon Park, Hiroaki Niiro, Shinya Tanaka, Yoshihiro Baba
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A stromal platform for robust expansion of functional IL-10–producing B cells for immune regulation
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Abstract
IL-10–producing B cells exert immunosuppressive effects, yet their low abundance and poor in vitro viability have limited their therapeutic application. Here, we developed a stromal coculture system using MS5 cells engineered to express human CD40L, BAFF, and IFN-β1 (MS5-3F, for “3 factors”), which enables robust induction and greater than 1000-fold expansion of human IL-10–producing B cells. The expanded cells showed phenotypic and transcriptional profiles characteristic of unswitched (IgM+) plasmablasts and potently suppressed CD4+ T cell proliferation in an IL-10–dependent manner. MS5-3F–expanded B cells also increased the frequency of regulatory T cells in vitro, an effect that was not abrogated by IL-10/IL-10R blockade, suggesting contributions from additional mechanisms. IL-10 production originated predominantly from naive B cells, rather than memory B cells. Furthermore, B cells from patients with systemic lupus erythematosus, despite impaired IL-10 production under conventional conditions, were efficiently differentiated into IL-10–producing B cells using this system. The expanded cells showed minimal IgG-secreting output. Our platform offers a scalable strategy for generating human regulatory B cells, laying the foundation for B cell–based immunotherapies.
Authors
Ryo Kawakami, Keisuke Imabayashi, Akemi Baba, Yuichi Saito, Kazuhiko Kawata, Yutaro Yada, Airi Shibata, Rinka Ito, Ryo Kurasawa, Ryota Higuchi, Sungyeon Park, Hiroaki Niiro, Shinya Tanaka, Yoshihiro Baba
Genetic regulation of
AIF1
shapes immune and liver injury profiles in chronic alcohol use
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
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Clinical Research and Public Health
Genetic regulation of
AIF1
shapes immune and liver injury profiles in chronic alcohol use
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Abstract
BACKGROUND In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation.METHODS Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single-nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles.RESULTS AIF1 transcript levels were genotype dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1+ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared with C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence.CONCLUSION These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD.TRIAL REGISTRATION ClinicalTrials.gov NCT02231840.FUNDING Research support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.
Authors
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Single-cell profiling reveals epithelial and immune responses in BK polyomavirus–infected human kidney biopsies
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
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Clinical Research and Public Health
Single-cell profiling reveals epithelial and immune responses in BK polyomavirus–infected human kidney biopsies
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Abstract
INTRODUCTION BK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood.METHODS In a cross-sectional study, single-cell RNA-seq from kidney allograft biopsies was used to assess cell type–specific responses between uninfected controls and 2 distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction).RESULTS Genes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally, enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV-infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models, likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient-derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection.CONCLUSION These not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.
Authors
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy
Ming Huang, Moritz Lassé, Silke Dehde, Felicitas E. Hengel, Fatih Demir, Anja M. Billing, Ning Song, Larissa Seifert, Oliver Kretz, Florian Grahammer, Ulf Panzer, Sebastian Brähler, Tobias B. Huber, Gunther Zahner, Markus M. Rinschen, Nicola M. Tomas
Ming Huang, Moritz Lassé, Silke Dehde, Felicitas E. Hengel, Fatih Demir, Anja M. Billing, Ning Song, Larissa Seifert, Oliver Kretz, Florian Grahammer, Ulf Panzer, Sebastian Brähler, Tobias B. Huber, Gunther Zahner, Markus M. Rinschen, Nicola M. Tomas
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Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy
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Abstract
Although the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a-KO (Thsd7a–/–) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins, such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins, and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. Thsd7a–/– mice only displayed a mild phenotype under basal conditions, and they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactome analysis identified a protein complex, including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.
Authors
Ming Huang, Moritz Lassé, Silke Dehde, Felicitas E. Hengel, Fatih Demir, Anja M. Billing, Ning Song, Larissa Seifert, Oliver Kretz, Florian Grahammer, Ulf Panzer, Sebastian Brähler, Tobias B. Huber, Gunther Zahner, Markus M. Rinschen, Nicola M. Tomas
Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ
Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W. Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S. Gallardo, Daniela L. Rebolledo, Felipe A. Court, Jerold Chun, Carlos P. Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan
Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W. Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S. Gallardo, Daniela L. Rebolledo, Felipe A. Court, Jerold Chun, Carlos P. Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan
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Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ
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Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid that signals through G protein–coupled receptors (LPA1–6) and regulates multiple cellular processes, including fibrosis. Although LPA signaling has been implicated in fibrotic diseases in several organs, its role in skeletal muscle remains unclear. Here, we show that LPA/LPA1 signaling promotes fibrogenesis after sciatic nerve transection. Denervation induces differential expression of LPA signaling axis components and a transient early increase in intramuscular LPA levels. Pharmacological inhibition of LPA1/3 with Ki16425, or genetic deletion of LPA1, reduces extracellular matrix accumulation and expansion of fibro/adipogenic progenitors (FAPs) in denervated muscle. Although LPA blockade suppresses atrophy-related gene expression, it does not fully preserve myofiber size. Mechanistically, denervation increases YAP/TAZ expression, nuclear localization in FAPs, and transcriptional activity, effects that are attenuated by LPA axis inhibition. Furthermore, pharmacological inhibition of YAP/TAZ with verteporfin reduces fibrosis after denervation, supporting their role as critical downstream mediators. Finally, transient denervation activates the LPA axis, promotes muscle fibrosis, reduces axonal density in the sciatic nerve, and increases neuromuscular junction instability, effects reversed by Ki16425. Together, these findings identify the LPA/LPA1/YAP/TAZ pathway as a key driver of denervation-induced muscle fibrosis and a potential therapeutic target in neuromuscular disorders.
Authors
Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W. Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S. Gallardo, Daniela L. Rebolledo, Felipe A. Court, Jerold Chun, Carlos P. Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan
Early-life viral infection generates pathological tissue-resident memory cells that contribute to asthma-like disease
Emma E. Brown, Jie Lan, Olivia B. Parks, Li Fan, Dequan Lou, Alysia McCray, Lisa Mathews, Alexander J. Wardropper, Anna Shull, Michelle L. Manni, Heth R. Turnquist, Kong Chen, Taylor Eddens
Emma E. Brown, Jie Lan, Olivia B. Parks, Li Fan, Dequan Lou, Alysia McCray, Lisa Mathews, Alexander J. Wardropper, Anna Shull, Michelle L. Manni, Heth R. Turnquist, Kong Chen, Taylor Eddens
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Early-life viral infection generates pathological tissue-resident memory cells that contribute to asthma-like disease
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Viral lower respiratory tract infections are common early in life and are associated with long-term development of asthma, a chronic condition defined by reversible airflow obstruction secondary to inflammation. Understanding the immunological mechanism connecting these two pathologies observed early in life becomes imperative to guide therapeutic measures. To investigate this connection, neonatal (days 4–6) or adult mice were infected with human metapneumovirus (HMPV) followed by a secondary HMPV infection 6 weeks later. Mice initially infected as neonates demonstrated increased mucus production, eosinophil recruitment, airway hyperresponsiveness, and Th2 T cell differentiation after rechallenge compared with adult mice rechallenged with HMPV. Neonatal HMPV infection led to formation of Th2 clonally expanded tissue-resident memory (TRM) T cells that were absent after adult HMPV. FTY720-mediated disruption of lymphocyte circulation demonstrated that TRMs contributed to pathology. Local depletion of lung CD4+ T cells and JAK2 inhibition mitigated pathology. These findings suggest TRMs uniquely generated after early-life viral infection can contribute to Th2-driven asthma pathology.
Authors
Emma E. Brown, Jie Lan, Olivia B. Parks, Li Fan, Dequan Lou, Alysia McCray, Lisa Mathews, Alexander J. Wardropper, Anna Shull, Michelle L. Manni, Heth R. Turnquist, Kong Chen, Taylor Eddens
High-dose influenza vaccine augments serological and cellular immunity of older people with HIV
Jonah Kupritz, Sheldon Davis, TianHao Liu, Prabhsimran Singh, Daniel Andrés Díaz-Pachón, Allan Rodriguez, Scott D. Boyd, Rajendra Pahwa, Suresh Pallikkuth, Savita G. Pahwa
Jonah Kupritz, Sheldon Davis, TianHao Liu, Prabhsimran Singh, Daniel Andrés Díaz-Pachón, Allan Rodriguez, Scott D. Boyd, Rajendra Pahwa, Suresh Pallikkuth, Savita G. Pahwa
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Clinical Research and Public Health
High-dose influenza vaccine augments serological and cellular immunity of older people with HIV
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Abstract
BACKGROUND High-dose influenza vaccine, containing 4 times more antigen than the standard dose, is recommended for people 65 years or older, but there is a knowledge gap surrounding its effect in people with HIV (PWH), who remain more vulnerable to serious influenza infections than people without HIV (PWoH) despite virological suppression. Our primary goal was to assess whether the high-dose vaccine improves antibody responses in PWH, especially older PWH.METHODS We assessed antibody responses to sequential high- versus standard-dose influenza vaccination in PWH. Young (18–40 years) PWoH (n = 55) and PWH (n = 37) and older (≥60 years) PWoH (n = 72) and PWH (n = 67) received a standard-dose vaccine during the 2020–2024 seasons, and 123 participants (41 older PWH) received a high-dose vaccine the subsequent season. All PWH were virologically suppressed on antiretroviral therapy. HA inhibition (HAI) titer and HA-specific IgG were analyzed at 0 to 180 days after vaccination; T cell activation–induced responses were assessed by flow cytometry.RESULTS All groups mounted significant HAI and IgG responses to all vaccine antigens at 28 days after standard- and high-dose vaccination. Responses to A/H1N1 were lower in magnitude and durability in older PWH compared with young PWoH after the standard dose and were not boosted with the high dose, whereas the high dose enhanced A/H3N2 and B/Victoria IgG, in addition to CD4+ T cell responses to all antigens, in older PWH.CONCLUSION Our data demonstrate partial efficacy of a high-dose vaccine in augmenting antibody responses of older PWH while highlighting limitations in boosting A/H1N1-specific responses.TRIAL REGISTRATION ClinicalTrials.gov NCT04487041.FUNDING NIH grant (5R01AG068110).
Authors
Jonah Kupritz, Sheldon Davis, TianHao Liu, Prabhsimran Singh, Daniel Andrés Díaz-Pachón, Allan Rodriguez, Scott D. Boyd, Rajendra Pahwa, Suresh Pallikkuth, Savita G. Pahwa
TNF-
blockade mitigates immune checkpoint–related nephritis in a humanized mouse model
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E.J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E.J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
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TNF-
blockade mitigates immune checkpoint–related nephritis in a humanized mouse model
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Abstract
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of IFN-γ and TNF-α pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with proinflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into 4 experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA-seq. Histology revealed increased renal infiltration of CD4+/CD8+ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA-seq revealed shifts in immune cell populations and genes of interest including Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and proinflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.
Authors
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E.J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression
Yan Tang, Stanislovas S. Jankauskas, Li Liu, Xujun Wang, Alus M. Xiaoli, Fajun Yang, Gaetano Santulli, Daorong Feng, Jeffrey E. Pessin
Yan Tang, Stanislovas S. Jankauskas, Li Liu, Xujun Wang, Alus M. Xiaoli, Fajun Yang, Gaetano Santulli, Daorong Feng, Jeffrey E. Pessin
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TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression
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Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using mice with whole-body and cardiomyocyte-specific TIGAR knockout, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin dependent, as double-knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increasing Parkin expression in multiple cell lines. Our findings reveal how early cardiac metabolism programs lifelong cardiac function through epigenetic mechanisms, and identify developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.
Authors
Yan Tang, Stanislovas S. Jankauskas, Li Liu, Xujun Wang, Alus M. Xiaoli, Fajun Yang, Gaetano Santulli, Daorong Feng, Jeffrey E. Pessin
Safety of a tetravalent live dengue virus vaccine in children responding to one serotype only
Laura J. White, Lindsay D. Hein, Maria Abad Fernandez, Cameron Adams, Elizabeth Adams, Emily Freeman, Ruby Shah, Lakshmanane Premkumar, Kristal An Agrupis, Maria Vinna Crisostomo, Jedas Veronica Daag, Michelle Ylade, Jacqueline Deen, Ana Lena Lopez, Leah Katzelnick, Aravinda M. de Silva
Laura J. White, Lindsay D. Hein, Maria Abad Fernandez, Cameron Adams, Elizabeth Adams, Emily Freeman, Ruby Shah, Lakshmanane Premkumar, Kristal An Agrupis, Maria Vinna Crisostomo, Jedas Veronica Daag, Michelle Ylade, Jacqueline Deen, Ana Lena Lopez, Leah Katzelnick, Aravinda M. de Silva
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Safety of a tetravalent live dengue virus vaccine in children responding to one serotype only
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Dengue virus (DENV) vaccines should be designed to induce balanced protective immunity to all 4 DENV serotypes to mitigate the risk of vaccine-enhanced dengue disease. The first tetravalent live DENV vaccine (Dengvaxia) tested in humans was efficacious in children who were partially immune to DENV at baseline. In DENV-naive children, the vaccine was not efficacious and placed some children at risk of more severe WT DENV breakthrough infections. To define dengue vaccine responses at the individual patient level and their relationship to mild and severe dengue infections, we prospectively studied a cohort of DENV-naive children who received 1 dose of Dengvaxia. The vaccine stimulated variable responses that neutralized 0, 1 (monotypic), or 2+ (multitypic) serotypes in individual children. Using a logistic regression model, we found that vaccinated children with neutralizing antibody (NAb) to 1 serotype only were at greater risk developing dengue compared with children who were not vaccinated (odds ratio 5.07). This risk was not observed in vaccinated children with no NAb or NAb to 2 or more serotypes. We propose that individuals with durable NAb to 1 serotype have an abundance of serotype cross-reactive, nonneutralizing antibodies implicated in the enhanced replication of heterologous serotypes.
Authors
Laura J. White, Lindsay D. Hein, Maria Abad Fernandez, Cameron Adams, Elizabeth Adams, Emily Freeman, Ruby Shah, Lakshmanane Premkumar, Kristal An Agrupis, Maria Vinna Crisostomo, Jedas Veronica Daag, Michelle Ylade, Jacqueline Deen, Ana Lena Lopez, Leah Katzelnick, Aravinda M. de Silva
RAS signaling in lung adenocarcinoma is defined by lineage context and
DUSP4
loss
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
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Clinical Research and Public Health
RAS signaling in lung adenocarcinoma is defined by lineage context and
DUSP4
loss
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BACKGROUND The molecular landscape of lung adenocarcinoma (LUAD) is often illustrated as a driver-oncogene pie chart, but identical mutations exhibit heterogeneous signaling shaped by comutations, transcriptional programs, and lineage context. We propose a lineage-integrated signaling framework using an EGFR mutation signature (mSig).METHODS We defined EGFR mSig using differentially expressed genes in EGFR-mutant (EGFR-mt) LUADs. Semisupervised clustering and machine learning models were used to test reproducibility in different combinations of datasets. We analyzed molecular subtypes, lineage markers, co-occurring mutations, and EGFR copy number alterations in EGFR mSig-defined subtypes of LUAD.RESULTS EGFR mSig showed robust classification performance (area under receiver operating characteristic curve = 0.83–0.95; mean negative predictive value = 96.3%). Validated gene expression subtypes and lung lineage markers were closely aligned with EGFR mSig status. Most EGFR mSig+ tumors, including many without EGFR mutations, belonged to the bronchioid subtype. A subset of canonical RAS mutations were mSig+ and mirrored the EGFR mutation pattern. EGFR WT/mSig– tumors were enriched for nonbronchioid subtypes and had comutations in TP53 or RAS/RAF/RTKs. We highlight a parsimonious collection of coordinated mutations, including RAS, KEAP1, STK11, TP53, and CDKN2A, that taken together suggest coordination of tumor signaling previously suggested but now reproduced and expanded.CONCLUSION A potentially novel EGFR mSig that captures the transcriptional footprint of EGFR activation revealed a subset of EGFR WT LUADs with mt-like features. mSig refines LUAD taxonomy beyond mutation-only pie-chart models by incorporating lineage and comutation context. Lineage-directed stratification with coalteration identifies clinically relevant groups across EGFR and RAS states and highlights treatment opportunities for patients currently considered oncogene-negative.FUNDING National Cancer Institute (NCI) U01CA272541, R01CA262296, U24CA264021, UG1CA233333, R01CA211939.
Authors
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
Atypical memory B cell clonal expansion and inflammatory programs associate with platelet-activating antibody development in COVID-19
Nathan Witman, Mei Yu, Yuqi Zhang, Kexin Gai, Yuhong Chen, Lu Zhou, Christine Nguyen, Wen Zhu, Yongwei Zheng, Shawn Jobe, Mary Beth Graham, Weiguo Cui, Demin Wang, Renren Wen
Nathan Witman, Mei Yu, Yuqi Zhang, Kexin Gai, Yuhong Chen, Lu Zhou, Christine Nguyen, Wen Zhu, Yongwei Zheng, Shawn Jobe, Mary Beth Graham, Weiguo Cui, Demin Wang, Renren Wen
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Atypical memory B cell clonal expansion and inflammatory programs associate with platelet-activating antibody development in COVID-19
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Patients with COVID-19 who develop platelet-activating antibodies represent a subset at heightened thrombotic risk, yet the immune features associated with this response remains to be defined. We applied single-cell RNA-seq of B and T cells, single B cell V(D)J-seq, and plasma cytokine and chemokine analysis to define immune signatures distinguishing patients who did (PEA+) or did not (PEA–) develop these antibodies. Patients positive for PEA showed prominent transcriptional enrichment of inflammatory, antigen presentation, and B cell receptor signaling pathways within antigen-experienced B cell subsets. Expanded B cell clones in patients positive for PEA were disproportionately enriched within atypical memory B cells and exhibited upregulated IFN-γ–response signatures, increased proliferative mutational patterns, limited class switching, and a significant overrepresentation of RKH/Y5 heavy-chain motifs associated with platelet-activating antibodies, consistent with an extrafollicular-biased response. Parallel T cell profiling revealed IL-12 pathway enrichment across most T cell subsets, increased IFN-γ transcription, and elevated plasma levels of Th1-associated cytokines in patients positive for PEA. Collectively, these data highlight a coordinated inflammatory environment marked by Th1-skewed T cell activation and selective expansion of atypical memory B cell clones carrying RKH/Y5 motifs, defining immunologic features associated with platelet-activating antibody development in COVID-19.
Authors
Nathan Witman, Mei Yu, Yuqi Zhang, Kexin Gai, Yuhong Chen, Lu Zhou, Christine Nguyen, Wen Zhu, Yongwei Zheng, Shawn Jobe, Mary Beth Graham, Weiguo Cui, Demin Wang, Renren Wen
Glucagon promotes net hepatic glycogen repletion following meal ingestion
Nidhi Kejriwal, David Bouslov, Cheyenne R. Castle, Riya S. Karve, Galina A. Arkharova, Ashot Sargsyan, Daniel J. Drucker, Guo-Fang Zhang, David A. D’Alessio, Jonathan E. Campbell, Megan E. Capozzi
Nidhi Kejriwal, David Bouslov, Cheyenne R. Castle, Riya S. Karve, Galina A. Arkharova, Ashot Sargsyan, Daniel J. Drucker, Guo-Fang Zhang, David A. D’Alessio, Jonathan E. Campbell, Megan E. Capozzi
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Glucagon promotes net hepatic glycogen repletion following meal ingestion
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Insulin and glucagon are described as having opposing actions on hepatic glycogen metabolism. However, here we showed that their coordinated action promoted glycogen turnover and meal glucose storage. In mice, pharmacological doses of insulin or glucagon failed to alter hepatic glycogen, but the combination produced a robust decrease in glycogen content. Additivity between insulin and glucagon was also seen with the activation of hepatic insulin signaling intermediates. This signaling pathway drove glycogen synthesis, suggesting concurrent actions on glycogen breakdown and repletion. A mixed nutrient meal, which stimulates an increase in both insulin and glucagon, enhanced the incorporation of dietary glucose into hepatic glycogen. This was much more pronounced than the effects of glucose alone, which only stimulated insulin secretion. These findings revealed that glucagon is required for efficient hepatic glucose storage when acting in concert with insulin. Coordinated insulin-glucagon signaling, thus, emerged as a critical mechanism for hepatic glycogen cycling, challenging the classical paradigm that these hormones work in opposition.
Authors
Nidhi Kejriwal, David Bouslov, Cheyenne R. Castle, Riya S. Karve, Galina A. Arkharova, Ashot Sargsyan, Daniel J. Drucker, Guo-Fang Zhang, David A. D’Alessio, Jonathan E. Campbell, Megan E. Capozzi
Semaglutide reduces murine blood pressure through the vascular smooth muscle GLP-1 receptor
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
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Semaglutide reduces murine blood pressure through the vascular smooth muscle GLP-1 receptor
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GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and proapoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in preconstricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.
Authors
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
Endothelial MHC expression is required to initiate T cell–mediated rejection of 3D-printed skin grafts
Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M. McNiff, Gwendolyn Davis, Richard A. Flavell, W. Mark Saltzman, Jordan S. Pober
Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M. McNiff, Gwendolyn Davis, Richard A. Flavell, W. Mark Saltzman, Jordan S. Pober
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Endothelial MHC expression is required to initiate T cell–mediated rejection of 3D-printed skin grafts
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Abstract
Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.
Authors
Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M. McNiff, Gwendolyn Davis, Richard A. Flavell, W. Mark Saltzman, Jordan S. Pober
Human antibody repertoire among kidney donors with and without HIV
Xianming Zhu, William R. Morgenlander, Diane M. Brown, Yolanda Eby, Megan Morsheimer, Jonah Odim, Serena M. Bagnasco, Meenakshi M. Rana, Sander S. Florman, Rachel J. Friedman-Moraco, Peter G. Stock, Alexander J. Gilbert, Shikha Mehta, Valentina Stosor, Sapna A. Mehta, Marcus R. Pereira, Catherine B. Small, Michele I. Morris, Jonathan Hand, Saima Aslam, Ghady Haidar, Maricar Malinis, Carlos A.Q. Santos, Joanna Schaenman, David Wojciechowski, Karthik Ranganna, Emily Blumberg, Nahel Elias, Josa A. Castillo-Lugo, Emmanouil Giorgakis, Senu Apewokin, M. Kate Grabowski, Dorry L. Segev, Andrew D. Redd, Christine M. Durand, H. Benjamin Larman, Aaron A.R. Tobian, on behalf of the HOPE in Action investigators
Xianming Zhu, William R. Morgenlander, Diane M. Brown, Yolanda Eby, Megan Morsheimer, Jonah Odim, Serena M. Bagnasco, Meenakshi M. Rana, Sander S. Florman, Rachel J. Friedman-Moraco, Peter G. Stock, Alexander J. Gilbert, Shikha Mehta, Valentina Stosor, Sapna A. Mehta, Marcus R. Pereira, Catherine B. Small, Michele I. Morris, Jonathan Hand, Saima Aslam, Ghady Haidar, Maricar Malinis, Carlos A.Q. Santos, Joanna Schaenman, David Wojciechowski, Karthik Ranganna, Emily Blumberg, Nahel Elias, Josa A. Castillo-Lugo, Emmanouil Giorgakis, Senu Apewokin, M. Kate Grabowski, Dorry L. Segev, Andrew D. Redd, Christine M. Durand, H. Benjamin Larman, Aaron A.R. Tobian, on behalf of the HOPE in Action investigators
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Clinical Research and Public Health
Human antibody repertoire among kidney donors with and without HIV
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Abstract
BACKGROUND Transplanting kidneys from donors with HIV to recipients with HIV has become standard clinical practice. However, donors with HIV may have higher prevalence of viral and bacterial infections and autoimmunity that could increase allograft rejection in recipients.METHODS We included deceased kidney donors (60 with HIV and 41 without HIV) who participated in a multicenter prospective study of HIV kidney transplantation between April 2018 and September 2021. Using phage immunoprecipitation sequencing, we compared the human antibody repertoire (allergens, autoantibodies, viruses, and bacterial toxins) between donors with and without HIV and evaluated their association with recipient allograft rejection. Moderated t tests were used to assess reactivity and a multivariate logistic regression model adjusted for donor sex and kidney donor profile index assessed the association between donor adenovirus reactivity and recipient allograft rejection.RESULTS Compared with donors without HIV, donors with HIV had lower BMI and were more likely to be African American. The median number of positive autoantibodies was marginally higher among donors with HIV (499 [IQR, 357, 579]) compared with that of donors without HIV (395 [IQR, 256, 538], P = 0.058). Donors with HIV additionally had significantly higher antibody reactivity to Epstein-Barr virus and cytomegalovirus (q < 0.05). Among all donors with and without HIV, antibodies against adenovirus were significantly associated with increased rejection among recipients, including after adjusting for false discovery (q < 0.05) and also adjusting for demographic factors using multivariable logistic regression (odds ratio = 4.97; 95% CI = 1.89–13.61).CONCLUSION The presence of antibodies against adenovirus infection in kidney donors with HIV may be associated with allograft rejection.TRIAL REGISTRATION ClinicalTrials.gov NCT03500315.FUNDING US NIH.
Authors
Xianming Zhu, William R. Morgenlander, Diane M. Brown, Yolanda Eby, Megan Morsheimer, Jonah Odim, Serena M. Bagnasco, Meenakshi M. Rana, Sander S. Florman, Rachel J. Friedman-Moraco, Peter G. Stock, Alexander J. Gilbert, Shikha Mehta, Valentina Stosor, Sapna A. Mehta, Marcus R. Pereira, Catherine B. Small, Michele I. Morris, Jonathan Hand, Saima Aslam, Ghady Haidar, Maricar Malinis, Carlos A.Q. Santos, Joanna Schaenman, David Wojciechowski, Karthik Ranganna, Emily Blumberg, Nahel Elias, Josa A. Castillo-Lugo, Emmanouil Giorgakis, Senu Apewokin, M. Kate Grabowski, Dorry L. Segev, Andrew D. Redd, Christine M. Durand, H. Benjamin Larman, Aaron A.R. Tobian, on behalf of the HOPE in Action investigators
Spatial proteomic mapping of the human and mouse retina using IBEX
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J. Chu
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J. Chu
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Spatial proteomic mapping of the human and mouse retina using IBEX
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Abstract
We generated a comparative spatial proteomic atlas of the human and mouse retina using a highly multiplexed immunohistochemistry technique called iterative bleaching extends multiplexity (IBEX). We refined the IBEX workflow by integrating an antibody dissociation option alongside chemical bleaching. This dual strategy enabled removal of the entire antibody complex, permitting the flexible use of antibodies from the same host species across iterative cycles. We coupled this workflow with super-resolution imaging via deconvolution and applied it to the retina of healthy humans and WT mice and the Crb1rd8 mouse model. We successfully imaged over 25 protein markers on human and mouse tissue sections, generating spatial atlases of the major retinal cell populations. Cross-species protein expression was compared to scRNA-seq datasets to identify protein and transcript disparities. Super-resolution IBEX delineated the ultrastructural features of the outer limiting membrane (OLM), identifying CD44 as a core structural component tightly colocalized with a highly organized F-actin belt within Müller glial endfeet. Using the Crb1rd8 mouse model, disruption of this complex was spatially associated with rosette formation and OLM structural failure. In summary, spatial proteomic atlases of the human and mouse retina were used to reveal insights into the arrangement of major retinal cell populations and OLM structure.
Authors
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J. Chu
Corrigendum
Corrigendum to: Autoreactive T cell receptors with shared germline-like α chains in type 1 diabetes
Peter S. Linsley, Fariba Barahmand-pour-Whitman, Elisa Balmas, Hannah A. DeBerg, Kaitlin J. Flynn, Alex K. Hu, Mario G. Rosasco, Janice Chen, Colin O’Rourke, Elisavet Serti, Vivian H. Gersuk, Keshav Motwani, Howard R. Seay, Todd M. Brusko, William W. Kwok, Cate Speake, Carla J. Greenbaum, Gerald T. Nepom, Karen Cerosaletti
Peter S. Linsley, Fariba Barahmand-pour-Whitman, Elisa Balmas, Hannah A. DeBerg, Kaitlin J. Flynn, Alex K. Hu, Mario G. Rosasco, Janice Chen, Colin O’Rourke, Elisavet Serti, Vivian H. Gersuk, Keshav Motwani, Howard R. Seay, Todd M. Brusko, William W. Kwok, Cate Speake, Carla J. Greenbaum, Gerald T. Nepom, Karen Cerosaletti
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Amended Article
Corrigendum to: Autoreactive T cell receptors with shared germline-like α chains in type 1 diabetes
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Authors
Peter S. Linsley, Fariba Barahmand-pour-Whitman, Elisa Balmas, Hannah A. DeBerg, Kaitlin J. Flynn, Alex K. Hu, Mario G. Rosasco, Janice Chen, Colin O’Rourke, Elisavet Serti, Vivian H. Gersuk, Keshav Motwani, Howard R. Seay, Todd M. Brusko, William W. Kwok, Cate Speake, Carla J. Greenbaum, Gerald T. Nepom, Karen Cerosaletti
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Endothelial GDF15 deficiency enhances barrier function and mitigates pulmonary fibrosis
Pulmonary fibrosis is frequently accompanied by pulmonary hypertension, which can occur disproportionate to the extent of fibrosis, suggesting a fibrosis-independent vascular remodeling process....
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Cell biology
Pulmonology
Vascular biology
Endothelial GDF15 deficiency enhances barrier function and mitigates pulmonary fibrosis
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Pulmonary fibrosis is frequently accompanied by pulmonary hypertension, which can occur disproportionate to the extent of fibrosis, suggesting a fibrosis-independent vascular remodeling process. Here, we demonstrated that plasma growth differentiation factor 15 (GDF15) is elevated across diverse fibrotic lung disease subtypes and correlates with markers of elevated right heart pressures, but not pulmonary function indices, indicating a possible link to endothelial cell dysfunction. To investigate the import of endothelial GDF15 as a modifier of lung fibrosis pathogenesis, we generated endothelial cell-specific Gdf15 knockout mice, which showed protection from bleomycin-induced lung injury and fibrosis, with preserved lung function. RNA sequencing of human pulmonary microvascular endothelial cells revealed altered expression of barrier-regulatory genes in GDF15-deficient endothelial cells compared to controls. Functional studies confirmed that GDF15 knockdown attenuates thrombin-induced barrier disruption by reducing cytosolic Ca2+ responses. Together, these findings implicate endothelial GDF15 as a modifier of vascular permeability and Ca2+ signaling, and a contributor to lung injury and fibrosis.
Authors
Kristen Raffensperger, Marta Bueno, Brian J. Philips, Megan Miller, Máté Katona, Shuai Yuan, Adriana Estrada-Bernal, Byron Chuan, Pavan Suresh, Stephanie Taiclet, Scott Hahn, Yingze Zhang, Jonathan K. Alder, Seyed Mehdi Nouraie, Daniel J. Kass, Oliver Eickelberg, Adam C. Straub
TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we...
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Cell biology
Metabolism
Pulmonology
TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor–β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine–glutamate–α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease.
Authors
Fei Li, Niv Vigder, David R. Ziehr, Mari Kamiya, Hung N. Nguyen, Diana E. Ferreyra Faustino, Aseel H. Khalil, Hilaire C. Lam, Matthew L. Steinhauser, Edy Y. Kim, William M. Oldham
In Vivo Characterization of Candida Extracellular Vesicles Reveals Unique Infection Pathway Proteins
Research Letter
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Microbiology
In Vivo Characterization of Candida Extracellular Vesicles Reveals Unique Infection Pathway Proteins
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Justin Massey, Robert Zarnowski, William Hartman Jr., Jeniel E. Nett, David R. Andes
GALNT1 drives aggressive phenotypes of rheumatoid synoviocytes via NEK9 O‑glycosylation
Fibroblast-like synoviocytes (FLSs) are crucial in driving synovial inflammation and joint damage in rheumatoid arthritis (RA). This study explored the functions and underlying mechanisms of...
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Bone biology
GALNT1 drives aggressive phenotypes of rheumatoid synoviocytes via NEK9 O‑glycosylation
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Fibroblast-like synoviocytes (FLSs) are crucial in driving synovial inflammation and joint damage in rheumatoid arthritis (RA). This study explored the functions and underlying mechanisms of GALNT1-mediated O-glycosylation, which is markedly upregulated in RA FLSs, in synovial aggression and subsequent experimental joint damage. Targeted suppression of GALNT1 effectively curtailed migration and invasion in RA FLSs and mitigated arthritis severity in a rat collagen-induced arthritis (CIA) model. Mechanistically, NEK9 was identified as a pivotal substrate and downstream effector of GALNT1, affecting the aggressive phenotype of RA FLSs. In vitro experiments further demonstrated that O-glycosylation of NEK9, mediated by GALNT1, promotes the pathogenic phenotype of RA FLSs by promoting cytoskeleton reorganization and restraining excessive endoplasmic reticulum (ER) stress activation. Our study provides mechanistic insights into the activation of RA FLSs and identifies GALNT1 as a potential therapeutic target for RA.
Authors
Yaoyao Zou, Haobo Lin, Jianling Su, Jieying Wang, Qin Zeng, Tianxiao Feng, Yunxia Lei, Jianda Ma, Hudan Pan, Hanshi Xu, Lie Dai, Yang Li
GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism
Aortic dissection (AD) is a catastrophic vascular emergency with high mortality, and current pharmacologic interventions to prevent its progression are limited. Vascular smooth muscle cells (VSMCs)...
Research
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Cardiology
Vascular biology
GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism
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Aortic dissection (AD) is a catastrophic vascular emergency with high mortality, and current pharmacologic interventions to prevent its progression are limited. Vascular smooth muscle cells (VSMCs) undergo a pathological phenotypic switch from a contractile to a synthetic state during AD, compromising aortic wall integrity; however, the underlying metabolic mechanisms remain poorly understood. In this study, we performed integrative transcriptomic analyses and identified glutaminase 1 (GLS1) as a key regulator of VSMC phenotypic switching in AD. GLS1 expression was significantly downregulated in VSMCs from both human AD aortic tissues and mouse models. Functionally, GLS1 deficiency promoted PDGF-BB–induced VSMC dedifferentiation in vitro. Smooth muscle cells specific Gls1 knockout (Gls1SMKO) mice exhibited aggravated AD upon BAPN treatment, whereas VSMCs specific GLS1 overexpression improved the contractile phenotype and reduced AD incidence. Mechanistically, GLS1 downregulation impaired glutamate metabolism, leading to reduced levels of glutathione and α-ketoglutarate. This metabolic disruption promoted reactive oxygen species accumulation and mitochondrial dysfunction, ultimately triggering VSMC phenotypic switching. Furthermore, we found that GLS1 transcription was repressed by retinoic acid receptor-α (RARα). Pharmacologic inhibition of RARα with AR7 restored GLS1 expression, ameliorated VSMC phenotypic switching, and conferred protection against AD. These findings reveal a critical role of GLS1-mediated glutamate metabolism in VSMC phenotypic switching and suggest a promising therapeutic strategy for AD.
Authors
Wei Xie, Chen Ning, Chen Lu, Dongjin Wang, Shuang Zhao, Tianyu Song, Hailong Cao
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