{"title":"CANE, a Component of the NLRP3 Inflammasome, Promotes Inflammasome Activation.","authors":"Naoe Kaneko, Mie Kurata, Toshihiro Yamamoto, Akimasa Sakamoto, Yasutsugu Takada, Hidetaka Kosako, Hiroyuki Takeda, Tatsuya Sawasaki, Junya Masumoto","doi":"10.4049/jimmunol.2300175","DOIUrl":"10.4049/jimmunol.2300175","url":null,"abstract":"<p><p>The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1β secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a \"speck\" in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1β secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow-derived macrophages of CANE-transgenic mice exhibited increased IL-1β secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"86-95"},"PeriodicalIF":3.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark P Murphy, David Hunt, Malcolm Herron, Jake McDonnell, Rashed Alshuhoumi, Lorcan P McGarvey, Aurelie Fabré, Helen O'Brien, Cormac McCarthy, S Lorraine Martin, Noel G McElvaney, Emer P Reeves
{"title":"Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation.","authors":"Mark P Murphy, David Hunt, Malcolm Herron, Jake McDonnell, Rashed Alshuhoumi, Lorcan P McGarvey, Aurelie Fabré, Helen O'Brien, Cormac McCarthy, S Lorraine Martin, Noel G McElvaney, Emer P Reeves","doi":"10.4049/jimmunol.2300658","DOIUrl":"10.4049/jimmunol.2300658","url":null,"abstract":"<p><p>In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"75-85"},"PeriodicalIF":3.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole C Guilz, Yong-Oon Ahn, Hijab Fatima, Luis Alberto Pedroza, Seungmae Seo, Rajesh Kumar Soni, Ning Wang, Dieter Egli, Emily M Mace
{"title":"Replication Stress in Activated Human NK Cells Induces Sensitivity to Apoptosis.","authors":"Nicole C Guilz, Yong-Oon Ahn, Hijab Fatima, Luis Alberto Pedroza, Seungmae Seo, Rajesh Kumar Soni, Ning Wang, Dieter Egli, Emily M Mace","doi":"10.4049/jimmunol.2300843","DOIUrl":"10.4049/jimmunol.2300843","url":null,"abstract":"<p><p>NK cells are innate immune effectors that kill virally infected or malignant cells. NK cell deficiency (NKD) occurs when NK cell development or function is impaired and variants in MCM4, GINS1, MCM10, and GINS4 result in NKD. Although NK cells are strongly impacted by mutational deficiencies in helicase proteins, the mechanisms underlying this specific susceptibility are poorly understood. In this study, we induced replication stress in activated NK cells or T cells by chemical and genetic methods. We found that the CD56bright subset of NK cells accumulates more DNA damage and replication stress during activation than do CD56dim NK cells or T cells. Aphidicolin treatment increases apoptosis of CD56bright NK cells through increased pan-caspase expression and decreases perforin expression in surviving cells. These findings show that sensitivity to replication stress affects NK cell survival and function and contributes to NKD.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"40-51"},"PeriodicalIF":3.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Skyler V Hendrix, Yassin Mreyoud, Michael E McNehlan, Asya Smirnov, Sthefany M Chavez, Brian Hie, Megan M Chamberland, Tara R Bradstreet, Ashlee M Webber, Darren Kreamalmeyer, Reshma Taneja, Bryan D Bryson, Brian T Edelson, Christina L Stallings
{"title":"BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms.","authors":"Skyler V Hendrix, Yassin Mreyoud, Michael E McNehlan, Asya Smirnov, Sthefany M Chavez, Brian Hie, Megan M Chamberland, Tara R Bradstreet, Ashlee M Webber, Darren Kreamalmeyer, Reshma Taneja, Bryan D Bryson, Brian T Edelson, Christina L Stallings","doi":"10.4049/jimmunol.2200819","DOIUrl":"10.4049/jimmunol.2200819","url":null,"abstract":"<p><p>Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to M. tuberculosis infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to M. tuberculosis infection, but how BHLHE40 impacts macrophage and dendritic cell responses to M. tuberculosis is unknown. In this study, we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a proinflammatory state and better control of M. tuberculosis infection. Loss of Bhlhe40 expression in murine bone marrow-derived myeloid cells cultured in the presence of GM-CSF results in lower levels of proinflammatory associated signaling molecules IL-1β, IL-6, IL-12, TNF-α, inducible NO synthase, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory-associated molecules MCP-1 and IL-10 following exposure to heat-killed M. tuberculosis. Deletion of Il10 in Bhlhe40-/- myeloid cells restored some, but not all, proinflammatory signals, demonstrating that BHLHE40 promotes proinflammatory responses via both IL-10-dependent and -independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of M. tuberculosis-infected Bhlhe40-/- mice exhibit defects in inducible NO synthase production compared with infected wild-type mice, supporting that BHLHE40 promotes proinflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during M. tuberculosis infection in vivo.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1766-1781"},"PeriodicalIF":3.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11105981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J Michael Stolley, Milcah C Scott, Stephen D O'Flanagan, Marco Künzli, Courtney A Matson, Eyob Weyu, Ryan A Langlois, Vaiva Vezys, David Masopust
{"title":"Cutting Edge: First Lung Infection Permanently Enlarges Lymph Nodes and Enhances New T Cell Responses.","authors":"J Michael Stolley, Milcah C Scott, Stephen D O'Flanagan, Marco Künzli, Courtney A Matson, Eyob Weyu, Ryan A Langlois, Vaiva Vezys, David Masopust","doi":"10.4049/jimmunol.2400010","DOIUrl":"10.4049/jimmunol.2400010","url":null,"abstract":"<p><p>Humans experience frequent respiratory infections. Immunology and vaccinology studies in mice are typically performed in naive specific pathogen-free animals responding to their very first respiratory challenge. We found that the first respiratory infection induces lifelong enlargement of the lung-draining mediastinal lymph nodes (medLNs). Furthermore, infection-experienced medLNs supported better naive T cell surveillance and effector responses to new unrelated infections that exhibited more biased accumulation and memory establishment within the lung. Moreover, we observed that weight loss induced by influenza infection was substantially reduced in mice that had recovered from a previous unrelated respiratory viral challenge. These data show that the lack of infectious history and corresponding medLN hypoplasia in specific pathogen-free mice alter their immune response to lung infections. Preclinical vaccination and immunology studies should consider the previous infectious experience of the model organism.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1621-1625"},"PeriodicalIF":3.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Renee R Anderko, Allison E DePuyt, Rhianna Bronson, Arlene C Bullotta, Evgenia Aga, Ronald J Bosch, R Brad Jones, Joseph J Eron, John W Mellors, Rajesh T Gandhi, Deborah K McMahon, Bernard J Macatangay, Charles R Rinaldo, Robbie B Mailliard
{"title":"Persistence of a Skewed Repertoire of NK Cells in People with HIV-1 on Long-Term Antiretroviral Therapy.","authors":"Renee R Anderko, Allison E DePuyt, Rhianna Bronson, Arlene C Bullotta, Evgenia Aga, Ronald J Bosch, R Brad Jones, Joseph J Eron, John W Mellors, Rajesh T Gandhi, Deborah K McMahon, Bernard J Macatangay, Charles R Rinaldo, Robbie B Mailliard","doi":"10.4049/jimmunol.2300672","DOIUrl":"10.4049/jimmunol.2300672","url":null,"abstract":"<p><p>HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1564-1578"},"PeriodicalIF":3.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kevin Doyoon Won, Lazaro Gil Gonzalez, Yoelys Cruz-Leal, Alequis Pavon Oro, Alan H Lazarus
{"title":"Antagonism of the Platelet-Activating Factor Pathway Mitigates Inflammatory Adverse Events Driven by Anti-erythrocyte Antibody Therapy in Mice.","authors":"Kevin Doyoon Won, Lazaro Gil Gonzalez, Yoelys Cruz-Leal, Alequis Pavon Oro, Alan H Lazarus","doi":"10.4049/jimmunol.2300638","DOIUrl":"10.4049/jimmunol.2300638","url":null,"abstract":"<p><p>Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts primarily due to antiplatelet autoantibodies. Anti-D is a donor-derived polyclonal Ab against the rhesus D Ag on erythrocytes used to treat ITP. Unfortunately, adverse inflammatory/hypersensitivity reactions and a Food and Drug Administration-issued black box warning have limited its clinical use. This underscores the imperative to understand the inflammatory pathway associated with anti-erythrocyte Ab-based therapies. TER119 is an erythrocyte-specific Ab with anti-D-like therapeutic activity in murine ITP, while also exhibiting a distinct inflammatory signature involving production of CCL2, CCL5, and CXCL9 but not IFN-γ. Therefore, TER119 has been used to elucidate the potential mechanism underlying the adverse inflammatory activity associated with anti-erythrocyte Ab therapy in murine ITP. Prior work has demonstrated that TER119 administration is associated with a dramatic decrease in body temperature and inflammatory cytokine/chemokine production. The work presented in the current study demonstrates that inhibiting the highly inflammatory platelet-activating factor (PAF) pathway with PAF receptor antagonists prevents TER119-driven changes in body temperature and inhibits the production of the CCL2, CCL5, and CXCL9 inflammatory cytokines in CD-1 mice. Phagocytic cells and a functional TER119 Fc region were found to be necessary for TER119-induced body temperature changes and increases in CXCL9 and CCL2. Taken together, this work reveals the novel requirement of the PAF pathway in causing adverse inflammatory activity associated with anti-erythrocyte Ab therapy in a murine model and provides a strategy of mitigating these potential reactions without altering therapeutic activity.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1531-1539"},"PeriodicalIF":4.4,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cole G Jensen, Jacob A Sumner, Steven H Kleinstein, Kenneth B Hoehn
{"title":"Inferring B Cell Phylogenies from Paired H and L Chain BCR Sequences with Dowser.","authors":"Cole G Jensen, Jacob A Sumner, Steven H Kleinstein, Kenneth B Hoehn","doi":"10.4049/jimmunol.2300851","DOIUrl":"10.4049/jimmunol.2300851","url":null,"abstract":"<p><p>Abs are vital to human immune responses and are composed of genetically variable H and L chains. These structures are initially expressed as BCRs. BCR diversity is shaped through somatic hypermutation and selection during immune responses. This evolutionary process produces B cell clones, cells that descend from a common ancestor but differ by mutations. Phylogenetic trees inferred from BCR sequences can reconstruct the history of mutations within a clone. Until recently, BCR sequencing technologies separated H and L chains, but advancements in single-cell sequencing now pair H and L chains from individual cells. However, it is unclear how these separate genes should be combined to infer B cell phylogenies. In this study, we investigated strategies for using paired H and L chain sequences to build phylogenetic trees. We found that incorporating L chains significantly improved tree accuracy and reproducibility across all methods tested. This improvement was greater than the difference between tree-building methods and persisted even when mixing bulk and single-cell sequencing data. However, we also found that many phylogenetic methods estimated significantly biased branch lengths when some L chains were missing, such as when mixing single-cell and bulk BCR data. This bias was eliminated using maximum likelihood methods with separate branch lengths for H and L chain gene partitions. Thus, we recommend using maximum likelihood methods with separate H and L chain partitions, especially when mixing data types. We implemented these methods in the R package Dowser: https://dowser.readthedocs.io.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1579-1588"},"PeriodicalIF":4.4,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julien Boucher, Caroline Gilbert, Santanu Bose, Philippe A Tessier
{"title":"S100A9: The Unusual Suspect Connecting Viral Infection and Inflammation.","authors":"Julien Boucher, Caroline Gilbert, Santanu Bose, Philippe A Tessier","doi":"10.4049/jimmunol.2300640","DOIUrl":"10.4049/jimmunol.2300640","url":null,"abstract":"<p><p>The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"212 10","pages":"1523-1529"},"PeriodicalIF":4.4,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11076006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danielle J Sisnett, Katherine B Zutautas, Jessica E Miller, Harshavardhan Lingegowda, Soo Hyun Ahn, Alison McCallion, Olga Bougie, Bruce A Lessey, Chandrakant Tayade
{"title":"The Dysregulated IL-23/TH17 Axis in Endometriosis Pathophysiology.","authors":"Danielle J Sisnett, Katherine B Zutautas, Jessica E Miller, Harshavardhan Lingegowda, Soo Hyun Ahn, Alison McCallion, Olga Bougie, Bruce A Lessey, Chandrakant Tayade","doi":"10.4049/jimmunol.2400018","DOIUrl":"10.4049/jimmunol.2400018","url":null,"abstract":"<p><p>Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1428-1441"},"PeriodicalIF":4.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}