IL-36 family cytokines mediate immune activation in Sjogren’s disease and may represent a novel biomarker of disease
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ORGANISM(S): Mus musculus
PROVIDER: GSE294030 | GEO | 2026/02/25
REPOSITORIES: GEO
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Project description:IL-36 family cytokines mediate immune activation in Sjogren’s disease and may represent a novel biomarker of disease
| PRJNA1247924 | ENA
Project description:Toll-like receptors (TLRs) are important mediators of chronic inflammation in numerous autoimmune diseases, although the role of these receptors in primary Sjögren’s syndrome (pSS) remains incompletely understood. Previous studies in our laboratory established Myd88 as a crucial mediator of disease, although the upstream signaling events that culminate in Myd88 activation have yet to be identified. To objective of this study was to identify specific Myd88-dependent TLR-related pathways that are dysregulated both locally and systemically in a mouse model of pSS (NOD.B10Sn-H2b/J (NOD.B10)). We performed RNA-sequencing on spleens derived from NOD.B10 mice. We then harvested salivary tissue and spleens from Myd88-sufficient and deficient C57BL/10 (BL/10) and NOD.B10 mice and performed flow cytometry to determine expression of Myd88-dependent TLRs. We then cultured splenocytes with TLR2 and TLR4 agonists and measured IL-6 secretion by ELISA. Next, we evaluated spontaneous and TLR4-mediated inflammatory cytokine secretion in NOD.B10 salivary tissue. Finally, we assessed spontaneous Myd88-dependent cytokine secretion by NOD.B10 salivary cells. We identified dysregulation of numerous TLR-related networks in pSS splenocytes, particularly those employed by TLR2 and TLR4. We found upregulation of TLRs in both the splenic and salivary tissue from pSS mice. In NOD.B10 splenic tissue, B cell TLR1, TLR2, and TLR6 expression was reduced to levels of BL/10 controls in the absence of Myd88. Splenocytes from NOD.B10 mice were hyper-responsive to TLR2 ligation and the endogenous molecule decorin modulated inflammation via TLR4. Finally, we found spontaneous secretion of numerous inflammatory cytokines and this was enhanced following TLR4 ligation in female NOD.B10 salivary tissue as compared to males. Moreover, we found that spontaneous production of salivary IL-6, MCP-1 and TNFa requires Myd88 in pSS salivary tissue. Thus, our data demonstrate that Myd88-dependent TLR pathways contribute to the inflammatory landscape in pSS, and inhibition of such will likely have therapeutic utility.
2020-01-08 | GSE136402 | GEO
Project description:Primary Sjogren’s disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Prior studies by our group showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. To this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10 Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10 Tlr-DKO). The objective of this study was to determine if Tlr9 mediated sex-biased disease and whether this was dependent on the expression of Tlr7.
2025-07-23 | GSE292271 | GEO
Project description:41K whole genome oligo-microarrays (Agilent Technologies) were used to characterize age-dependent changes in gene expression in pancreatic lymph nodes (PLN) obtained from up to 7 individual NOD mice at 6 different time points (10 days (n=7), and 4 weeks (n=6), 8 weeks (n=4), 12 weeks (n=7), 16 weeks (n=6), and 20 weeks of age (n=5)), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D. NOD/LtJ (NOD), NOD.B10Sn-H2b/J (NOD.B10) female mice of multiple ages were used for this study. Six Groups of NOD mice were sacrificed at 10 days, and 4, 8, 12, 16, and 20 weeks of age and pancreatic lymph nodes (PLN) were removed and prepared for mRNA analysis. Two Groups of 10 NOD.B10 mice [10 days (n=10) + 20 weeks of age (n=10)] were used as a tissue specific control. Gene (mRNA) expression was analyzed using the 41K Whole Mouse Genome Oligo Microarray Kit (Agilent Technologies), and gene expression data are processed (cy3: NOD, cy5: NOD.B10) and reported as normalized expression ratios: Log 10 (NOD processed signal / NOD.B10 processed signal) (Log ratio). 10days of age; PLN_10d (n=7), 4 weeks of age; PLN_4w (n=6), 8 weeks of age; PLN_8w (n=4), 12 weeks of age; PLN_12w (n=7), 16 weeks of age; PLN_16w (n=6), 20 weeks of age; PLN_20w (n=5)
2009-03-10 | E-GEOD-15150 | biostudies-arrayexpress
Project description:41K whole genome oligo-microarrays (Agilent Technologies) were used to characterize age-dependent changes in gene expression in peripheral blood cells (PBC) obtained from up to 8 individual NOD mice at 6 different time points (10 days (n=8), and 4 weeks (n=3), 8 weeks (n=7), 12 weeks (n=8), 16 weeks (n=7), and 20 weeks of age (n=4)), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D. NOD/LtJ (NOD), NOD.B10Sn-H2b/J (NOD.B10) female mice of multiple ages were used for this study. Six Groups of NOD mice were sacrificed at 10 days, and 4, 8, 12, 16, and 20 weeks of age and peripheral blood cells (PBC) were removed and prepared for mRNA analysis. Two Groups of 10 NOD.B10 mice [10 days (n=10) + 20 weeks of age (n=10)] were used as a tissue specific control. Gene (mRNA) expression was analyzed using the 41K Whole Mouse Genome Oligo Microarray Kit (Agilent Technologies), and gene expression data are processed (cy3: NOD, cy5: NOD.B10) and reported as normalized expression ratios: Log 10 (NOD processed signal / NOD.B10 processed signal) (Log ratio). 10days of age; PBC_10d (n=8), 4 weeks of age; PBC_4w (n=3), 8 weeks of age; PBC_8w (n=7), 12 weeks of age; PBC_12w (n=8), 16 weeks of age; PBC_16w (n=7), 20 weeks of age; PBC_20w (n=4)
2010-06-09 | E-GEOD-21897 | biostudies-arrayexpress
Project description:The IL-36 family of cytokines were identified in the early 2000's as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.
| S-EPMC8651476 | biostudies-literature
Project description:BackgroundGeneralized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory and warrant a better understanding of GPP pathogenesis.ObjectiveWe sought to understand better the disease mechanism of GPP to allow improved targeted therapies.MethodsWe performed a gene expression study on formalin-fixed paraffin-embedded GPP (n = 28) and PV (n = 12) lesional biopsies and healthy control (n = 20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with quantitative RT-PCR and immunohistochemistry, and a potential disease mechanism was investigated using primary human cell culture.ResultsCompared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes, respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36, and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and IFN-γ mRNA expression than PV lesions did. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules, and we show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G, respectively, were upregulated in both diseases and inhibited activation of IL-36.ConclusionsOur data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.
| S-EPMC5494022 | biostudies-literature
Project description:BackgroundThe IL-36 subfamily, a member of the IL-1 superfamily, is thought to promote type 2 (T2) and non-T2 inflammation and involved in autoimmune and airway disease progression. However, its role in asthma remains unclear.ObjectiveWe sought to determine the contribution of the IL-36 subfamily to the clinical manifestation of asthma.MethodsThe levels of serum IL-36α, IL-36β, and IL-36γ, recognized as IL-36 subfamily agonists, and IL-36 receptor antagonist (IL-36Ra) and IL-38, recognized as IL-36 subfamily antagonists, were measured by ELISA in 110 asthma patients (55 with nonsevere and 55 with severe asthma) aged ≥20 years and 31 healthy individuals. The association of IL-36 with clinical indices and inflammatory mediators was examined. The characteristics of high and low IL-36 subgroups were explored.ResultsIL-36α, IL-36γ, and IL-36Ra levels were significantly higher in asthma patients, especially patients with severe asthma, than in healthy controls. The high IL-36γ group exhibited lower Asthma Control Test scores (P = .01), more frequent asthma exacerbations (AEs), and higher hazard ratio for AEs. The high IL-36Ra group exhibited higher values of forced expiratory volume in 1 second, more frequent severe AEs, and higher hazard ratio for severe exacerbations. The IL-36 cytokine levels, except for IL 36α, were positively correlated with IL-6, IL-13, IL-17, and/or IFN-γ levels. IL-36Ra was positively correlated with age-adjusted forced expiratory volume and forced vital capacity.ConclusionA systemically high IL-36 level is associated with asthma severity and with both T2 and non-T2 cytokines, and it implies poor condition and enhancement of risk of AEs in asthma patients.
| S-EPMC11925522 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (n = 23) of long-term smokers with and without COPD in vivo and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components in vitro. Pulmonary macrophages were stimulated with IL-36 cytokines in vitro, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components in vitro. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. In vitro, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.
| S-EPMC7874394 | biostudies-literature
Project description:Meningeal lymphatic system governs immune cell trafficking in the brain via brain-to-cervical lymph node (CLN) pathway. However, the role of meningeal lymphatics in brain–CLN axis after stroke remains unclear. Here, we showed that meningeal lymphatic ablation (MLA) reduced brain infarct and neuronal loss levels and inhibited inflammatory pathways in the hippocampus after MCAO–reperfusion. Single-cell transcriptome analysis demonstrated that MLA reduced monocyte/macrophage and polymorphonuclear cell counts and T and natural killer cell effector function. MLA reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN LECs and downregulated expression of the CCN1 in floor LECs. Mechanistically, MLA inhibited inflammatory macrophage infiltration by repressing CCN1 and CD147 (thromboinflammatory marker) expression in blood vessels, thus inhibiting detrimental inflammatory responses. Blockade of VEGF-C-mediated signaling in meningeal lymphatic system improved memory function after ischemic stroke. Collectively, MLA reprograms the LEC transcriptome and inhibits CCN1-mediated proinflammatory responses during poststroke brain–CLN signaling.
2025-10-24 | GSE216703 | GEO