Inflammation
Abstract
Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) are characterized by impaired intestinal epithelial barrier (IEB) function. Alterations in the desmosomal cadherin desmoglein 2 (Dsg2) have been linked to loss of IEB and intestinal inflammation in IBD. We investigated the pathogenic impact of a cytoplasmatic-truncating mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in an IBD patient. Genetic analysis of a CD patient revealed a likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. Generation of an enterocyte-specific mouse model to recapitulate the human mutation resulted in a lethal intestinal barrier defect which was evident in homozygous but not in heterozygous mice. In vitro, barrier defects correlated with changes in Dsg2 mobility and upregulation of pore-forming tight junction protein claudin-2. Organoids derived from heterozygous Dsg2 truncated mice exhibited increased epithelial susceptibility to proinflammatory cytokines. Bulk RNAseq followed by gene ontology analysis in homozygous mice revealed a skewed IL17/IL23 response overlapping with transcriptional changes in patients with CD. Furthermore, 16S rRNA sequencing revealed alterations in microbiome composition in animals that carried the Dsg2 truncation. In summary, a patient-derived mutation in the DSG2 gene causing cytoplasmic truncation in homozygous state induced a lethal intestinal barrier breakdown in mice paralleled by altered gut microbiota and intestinal immune response.
Authors
Daniela Kugelmann, Alexander García-Ponce, Nadja Thielemann, Mariya Y. Radeva, Maresa Anders, Da Eun Kang, Christian Siadjeu, Natalie Burkard, Anja K.E. Horn, Jessica Neubauer, Matthias Hiermaier, Desalegn T. Egu, Christoph Schmitz, Oliver Kurzai, Katri S. Vuopala, Outi Kuismin, Nicolas Schlegel, Jens Waschke
Abstract
In chronic infection, T cell clones recognizing the same epitope are variably expanded, with some clones evolving to become dominant, while others are lost. Clonal expansion and changes in the repertoire reflect both T cell receptor–intrinsic (TCR-intrinsic) and -extrinsic factors, yet the individuality of TCR repertoires makes it difficult to disentangle how TCR sequence shapes clonal behaviors. To address this, we exploited the observation that TCRs can be grouped into clusters based on sequence similarity. Using complementarity-determining region 3β (CDR3β) sequencing data derived from lymphocytic choriomeningitis virus–specific CD8+ T cells from mice infected early and late in the course of chronic infection, we identified CDR3β clusters ubiquitously shared by all mice. The pattern of CDR3β cluster abundance was highly similar between mice at the early time point in both self-limiting and persistent infection models. Over the course of chronic infection, the pattern of cluster abundance diverged between mice and dominant clones emerged that did not share sequence similarity between mice. This repertoire divergence was not observed in self-limiting infection, where the pattern of cluster abundance established early in infection was stable between mice beyond resolution of infection. In chronic infection, the repertoires of stem-like and exhausted antigen-specific T cells remained similar over time within individual mice, suggesting clonal selection acts on the stem-like pool. Our findings suggest that antigen-specific CD8+ T cell clones expanded early in infection have CDR3β motifs that are shared between mice, supporting a role for TCR structural properties in determining the repertoire structure. Divergent patterns of repertoire composition later in chronic infection suggest that these shared CDR3β motifs are less important in patterning the repertoire than during the initial response and there is greater complexity in factors that sculpt the repertoire over the course of persistent antigen exposure.
Authors
Daniel Y. Chang, Barbara Bravi, Sakshi Malik, Donald J. McGuire, Hasan Ahmed, Rustom Antia, Rafi Ahmed, Ehsan Ghorani
Abstract
Obesity induces pathological remodeling of white adipose tissue (WAT), including chronic inflammation and fibrosis, which drive metabolic dysfunction. Although weight loss (WL) is the cornerstone of obesity treatment and improves systemic metabolic health, its effect on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional WL, we show that visceral WAT (vWAT) failed to fully recover despite normalization of body weight and marked metabolic improvement. Notably, vWAT fibrosis persisted and continued to progress after WL. This occurred while extracellular matrix (ECM) production by adipose progenitor cells was markedly reduced following WL, explaining why pharmacological inhibition of ECM synthesis fails to prevent fibrosis during WL. Instead, we observed impaired collagen degradation by both progenitor cells and macrophages, along with lysosomal dysfunction, during WL. This suggests that defective ECM degradation, rather than continued ECM production, underlies fibrosis persistence and aggravation during WL. Together, these findings identify impaired collagenolysis as a critical barrier to adipose tissue recovery after WL and suggest that enhancing ECM clearance, rather than inhibiting ECM synthesis, may represent a more effective therapeutic strategy to restore adipose tissue function.
Authors
Clémentine Rebière, Amanda Oliveira, Sébastien Dussaud, Iman Haddad, Agatha Assis-Ferreira, Adma M. Babetto, Christine Rouault, Fatiha Merabtene, Cheïma Benbida, Jimon Abatan, Simone Vargas da Silva, Laís Bhering Martins, Licia Torres, Ana Letícia M. Silveira, Cindy Rose, Laurent Genser, Fabrizio Andreelli, Isabelle Dugail, Marina Chaves de Oliveira, Joelle Vinh, Simon Lecoutre, Adaliene V.M. Ferreira, Karine Clément, Emmanuel L. Gautier, Genevieve Marcelin
Abstract
Osteoarthritis (OA) is a heterogeneous disease in which synovial inflammation drives structural progression and pain, yet the molecular diversity of synovitis remains poorly defined. Here, we performed a multimodal characterization of synovial tissues from 48 dogs with naturally occurring OA, integrating histopathology, immunohistochemistry, transcriptomics, MRI, and soluble mediator profiling. This analysis identified three discrete synovial pathotypes, pauci-immune, diffuse myeloid, and lympho-myeloid, defined by distinct immune cell composition and transcriptional programs reflecting biologically distinct endotypes. The lympho-myeloid pathotype, characterized by ectopic lymphoid structures and adaptive immune enrichment, was independently associated with greater structural joint damage on MRI despite comparable clinical scores, demonstrating that tissue stratification captures heterogeneity invisible to clinical assessment alone. Composite soluble mediator signatures correlated with disease severity across pathotypes. Cross-species analyses integrating a large human synovial cohort revealed conserved pathotype architecture and shared gene networks, including tyrosine kinase signaling and B cell receptor activation, validating the translational relevance of the canine model. Together, these findings provide a framework for patient stratification and therapeutic target discovery in OA, with broad implications for precision medicine within a One Medicine perspective.
Authors
Anaëlle Drieu-Vincent, Julien De Lima, Floriane M. Etienne, Romain Guiho, Noémie Podevin, Richard Danger, Florence Lezin, Nicolas Gaigeard, Sophie Allain, Jérôme Abadie, Thomas Rousseau, Pierre Maitre, Olivier Gauthier, Jérôme Guicheux, Marion S. Fusellier, Marie-Astrid Boutet
Abstract
Targeted injury to the biliary epithelium and impaired bile flow are central mechanisms underlying childhood cholangiopathies. In biliary atresia (BA), immune-mediated cholangiocyte injury drives progressive bile duct obstruction, yet epithelial-intrinsic programs regulating injury susceptibility remain incompletely defined. Here, we modeled virus-epithelium interactions using rhesus rotavirus (RRV) infection of human liver-derived cholangiocyte organoids from normal donors (NCO) and infants with BA at diagnosis (BACO-Dx) or transplantation (BACO-Tx). Compared with NCO, BA organoids displayed baseline defects in tight junction architecture and barrier function, with prominent epithelial disruption and apoptosis following RRV exposure. Transcriptomic profiling revealed that while NCO and BACO-Dx mounted predominantly interferon-associated antiviral responses, BACO-Tx exhibited an expanded inflammatory program characterized by enrichment of NF-κB (RELA/NFKB1) regulatory network at baseline and amplified by infection. Inhibition of NF-κB signaling with the hydrogen sulfide donor GYY4137 restored organoid growth, improved tight junction organization, reduced permeability, and attenuated RRV-induced apoptosis. In the murine BA model, GYY4137 improved disease severity, preserved bile duct architecture, and protected epithelial junctional integrity while limiting cholangiocyte apoptosis. These findings identify an epithelial NF-κB-predominant program as a key determinant of intrinsic susceptibility to viral injury in BA and support targeting cholangiocyte NF-κB signaling to suppress disease progression.
Authors
Wenqi Li, Ashley Fonseca-Mejia, Reena Mourya, Pavithra Sudhakara, Pranavkumar Shivakumar, Jorge A. Bezerra
Abstract
Castleman disease (CD) is an inflammatory disorder characterized by lymphadenopathy with distinctive histologic features, yet its pathophysiology remains poorly understood. This delays diagnoses and limits treatments, leading to additional morbidity and mortality. We used single- cell and spatial transcriptomics to characterize lymph nodes from unicentric CD (UCD) compared with non-specific inflammatory lymphadenopathies. While hematopoietic cells showed few compositional or transcriptional differences, lymph node stromal cells exhibited marked alterations in UCD, most notably an increased abundance of vascular smooth muscle cells (VSMCs) and broadly increased stromal signaling activity. A generalized linear model distinguished histologically indeterminate lymph nodes resembling UCD from non-specific inflammation most accurately using stromal rather than hematopoietic cell composition. Immunohistochemical staining for the VSMC marker CD146 (Melanoma Cell Adhesion Molecule, MCAM) further discriminated UCD from other causes of lymphadenopathy. Together, these findings identify increased VSMC abundance as a hallmark of UCD and suggest that this stromal signature can be leveraged to improve pathologic diagnosis and patient stratification.
Authors
Joshua D. Brandstadter, Samuel Meili, Joseph Zinski, Hung-Wei Cheng, Dorottya Laczko, Michael V. Gonzalez, Subin S. George, Megan S Lim, Adam Bagg, Yves Stanossek, Lucas Onder, Mechthild Lϋtge, Angelina De Martin, Bridget Austin, Melanie Mumau, Katherine S. Forsyth, Vinodh Pillai, Antonio Ferreira, Jon C. Aster, Sunita Nasta, Burkhard Ludewig, David C. Fajgenbaum, Ivan Maillard
Abstract
The inflammasome is an innate immune complex responsible for aberrant interleukin-1β (IL-1β) signaling in numerous chronic inflammatory diseases, including gout and Alzheimer’s disease. The inflammasome is composed of several proteins, including the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). We developed vaccines targeting various regions of ASC using a Qβ virus-like particle (VLP) platform to assess the efficacy of anti-ASC antibodies for inhibiting inflammasome activity. Using a mouse model of gout, we assessed seven vaccines targeting mouse ASC for their ability to reduce inflammasome activation and neutrophil responses. Three vaccines targeting different regions of the ASC protein (pyrin domain, linker region, and the caspase activation and recruitment domain) successfully targeted ASC, reduced IL-1β, and reduced neutrophil activation. Combining these three vaccines into one cocktail vaccine yielded similar efficacy in the gout model with a favorable safety profile. The combined ASC vaccine also reduced inflammasome levels and pathologically phosphorylated tau in a transgenic mouse model of tauopathy and did not significantly impair host immune responses to bacterial or viral infections. Thus, Qβ-VLP vaccines against ASC can neutralize pathological inflammasome activity across multiple inflammatory disease models.
Authors
Jonathan Hulse, Zachary Villaseñor, Samuel Kress, Kathryn Sánchez, Julianne Peabody, Kimberly A. Morrissey, Alan McNolty, Benjamin Lantz, Laura Gonzalez Bosc, Judy L. Cannon, Seth Daly, Bryce Chackerian, Kiran Bhaskar
Abstract
Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors, often including an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed baseline NK-cytopenia and CTL activation resembling MAS-susceptible patients. NK transcriptomes reflected IL-18/IFNg-axis activation and cell cycle upregulation. LCMV infection of Il18tg mice causes HLH/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox, Il18tg NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected Il18tg mice then developed signs of HLH/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice partially rescued virus-specific CTL responses, viral control, and survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.
Authors
Jemy A. Varghese, Leonardo Huang, Stephen D. Carro, Emily E. Landy, Anastasia Frank-Kamenetskii, Hannah Klinghoffer, Jeremy A. Morrissette, Vinh Dang, Laurence C. Eisenlohr, Scott W. Canna
Abstract
Persistent production of type I interferons (IFN-Is) is a hallmark of cutaneous lupus erythematosus (CLE). Ultraviolet (UV) light stimulates IFN-I response in the skin and exacerbates CLE. Here, we identify V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) as a negative regulator of both basal and UV-induced IFN-I response in the skin and show that VISTA limits skin photosensitivity in an IFN-I-dependent manner, in part through Stimulator of Interferon Genes (STING). Furthermore, we demonstrate a novel role for VISTA in keratinocytes both at steady state and in response to UV light. Conditional deletion of VISTA in epidermal keratinocytes results in a ~10-fold increase in basal skin IFN-I scores and a heightened UV-induced skin injury score, both of which are dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress the UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA in vivo, thereby reducing UV-induced skin injury scores. Together, these findings identify VISTA as a keratinocyte-intrinsic checkpoint that restrains STING-associated IFN-I response in the skin and suggest VISTA agonism as a therapeutic strategy to limit photosensitivity in CLE.
Authors
Zachary T. Peters, Lindsay K. Mendyka, J'Voughnn A. Blake, Himanshu B. Goswami, Angelique N. Cortez, Grace E. Crossland, Sicong Shan, Elizabeth C. Nowak, Myana Keusch, Mrinal K. Sarkar, Johann E. Gudjonsson, Christopher M. Burns, Dorothea T. Barton, Bruce R. Blazar, Tyler J. Curiel, Rodwell Mabaera, Victoria P. Werth, Andrea Kalus, Keith B. Elkon, Randolph J. Noelle, Sladjana Skopelja-Gardner
Abstract
BACKGROUND. Long-COVID, or post-acute sequelae of COVID-19 (PASC), leads to debilitating physical and cognitive deficits. No PASC molecular signature present in patients with diverse symptoms has been described. While PASC engages pathways regulating pro-fibrotic programs, no comparison of PASC with fibrosis-associated epigenetic landscapes has been reported at the bulk or single-cell level. We hypothesize that a subset of DNA methylation changes are present in PASC patients from multiple cohorts, predominate in specific immune or inflammatory cell-types, and overlap with the epigenetic profile of patients at risk of pulmonary fibrosis. METHODS. Two distinct prospective cohorts, in 2021 and in 2022-24, involving 203 patients with PASC underwent bulk whole genome methylation sequencing (WGMS). Single-cell WGMS data was generated from an independent PASC cohort. Sixty-eight pre-pandemic patients with conditions elevating risk of pulmonary fibrosis development were compared with PASC. RESULTS. Sixteen differentially methylated regions distinguished PASC versus multiple independent, healthy controls. Single-cell analysis of these regions indicated trending relative hypermethylation at multiple cell types, with T4 lymphocytes eliciting hypermethylation at most of the sequences identified to be PASC-specific DMRs in the bulk analysis. Patients at risk of pulmonary fibrosis development elicited DNA methylation changes overlapping PASC. CONCLUSION. In two independent prospective cohorts, blood WGMS identifies differentially methylated regions associated with PASC. Hypermethylation of these regions is predominantly, although not exclusively, associated with T4 lymphocytes and overlap with changes present in pre-pandemic pulmonary fibrosis at-risk patients. FUNDING. National Institutes of Health award HL160661 (AJ); and AI173035 (AJ and RSA).
Authors
Andy Madrid, Joseph Balnis, Lisa A. Drake, Anupama Tiwari, Vraj J. Patel, Paul J. Feustel, Jihua Liu, Sündüz Keleş, Fangxiu Xu, Chris L. Wright, Alvaro G. Hernandez, Recai Yucel, Marc A. Judson, Harold A. Singer, Reid S. Alisch, Ariel Jaitovich
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