IL-36 Amplifies Neutrophilic Lung Inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA667850 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12786056.fastq.gz | Fastqsanger.gz | |||
| SRR12786057.fastq.gz | Fastqsanger.gz | |||
| SRR12786058.fastq.gz | Fastqsanger.gz |
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Project description:IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we performed single-cell RNA-seq on an acute LPS mouse model of lung inflammation to provide insights into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. We identified neutrophils as a source of IL-36 which provides a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
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Project description:Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
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Project description:IL-23-Th17 signaling axis is responsible for neutrophilic inflammation in various barrier tissues. However, mechanistic links between IL-23 and Th17 activation remain unclear, despite of their critical contribution to chronic inflammatory diseases. Here, we discovered a novel signaling pathway linking IL-23 to Th17 activation in our neutrophil-dominant asthma (NDA) model. Through single-cell multi-omics analysis, we identified distinctive CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23. CD39+CD9+ IMs increased by IL-23p19 inhibitor suppressed NETosis, which inhibited Th17 activation. To inhibit NETosis, CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP molecules near neutrophils in a CD39-dependent manner. Thus, our discovery of CD39+CD9+ IMs provides previously unrecognized signaling component linking IL-23 and NETosis for controlling Th17 activation/neutrophilic inflammation. We finally demonstrated the decreased number of CD39+CD9+ immune cells in patients with severe chronic rhinosinusitis and inflammatory bowel disease, suggesting CD39+CD9+ IMs as potential therapeutic targets for IL-23-Th17-mediated inflammatory diseases.
2024-08-30 | GSE222456 | GEO
Project description:IL-23-Th17 signaling axis is responsible for neutrophilic inflammation in various barrier tissues. However, mechanistic links between IL-23 and Th17 activation remain unclear, despite of their critical contribution to chronic inflammatory diseases. Here, we discovered a novel signaling pathway linking IL-23 to Th17 activation in our neutrophil-dominant asthma (NDA) model. Through single-cell multi-omics analysis, we identified distinctive CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23. CD39+CD9+ IMs increased by IL-23p19 inhibitor suppressed NETosis, which inhibited Th17 activation. To inhibit NETosis, CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP molecules near neutrophils in a CD39-dependent manner. Thus, our discovery of CD39+CD9+ IMs provides previously unrecognized signaling component linking IL-23 and NETosis for controlling Th17 activation/neutrophilic inflammation. We finally demonstrated the decreased number of CD39+CD9+ immune cells in patients with severe chronic rhinosinusitis and inflammatory bowel disease, suggesting CD39+CD9+ IMs as potential therapeutic targets for IL-23-Th17-mediated inflammatory diseases.
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2022-07-31 | GSE179622 | GEO
Project description:Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ, thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, which was inhibited by exogenous IL-36Ra. The use of a therapeutic antibody that inhibits binding to the IL-36R attenuated IL-36γ-driven inflammation and cellular crosstalk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and have shown that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising therapeutic strategy in the treatment of COPD.
| S-EPMC9462491 | biostudies-literature
Project description:Alcohol associated hepatitis (AH) is characterized by neutrophilic inflammation leading to liver injury. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates hepatic regeneration and hepatic acute phase responses. In the liver IL-6 can signal through either membrane-bound or soluble IL-6 receptors (IL-6R).Aims:to determine the role of IL-6 trans signaling in the pathogenesis of alcohol-associated hepatitis.Methods:Using human liver RNA-Seq, we compared expression of IL-6 signaling pathway components in 51 patients with no liver disease (N=10), early alcohol-related steatohepatitis (early ASH, N=12), non-severe AH (N=11) and severe AH (N=18). Ingenuity Pathway Analysis was used to determine upstream regulators of IL-6 receptor expression. For in vitro studies, HepG2 cells were cultured overnight with either TGF-β1 (5 ng/ml) or 1% FBS, and STAT3 was activated with either 1) IL-6 to simulate classical signaling or 2) hyper-IL-6, a recombinant IL-6/IL-6Rα peptide that selectively activates trans-IL-6 signaling. RNA-Seq was performed on stimulated cells to define an IL-6 trans-signaling gene signature. This signature was used to define a patient subset with high IL-6TS activity (IL-6TS high). For in vivo studies, female mice 14-16 years old were treated with a 10 day chronic-plus binge ethanol liver injury model.Results:Human liver RNA-Seq data demonstrated declining IL-6R expression with progressively increasing severity, and pathway analysis of 3,513 differentially expressed genes identified TGF-β1 as the strongest negative upstream regulator of IL-6R expression in AH. Despite reduced IL-6R expression, STAT3-dependent gene expression was enhanced in severe AH. In vitro, TGF-β1 suppressed STAT3 phosphorylation by both classical and trans IL-6 signaling. However, only high-dose hyper-IL-6 (20 ng/ml) restored STAT3 activation, while TGF-β1-mediated suppression of STAT3 persisted despite high-dose IL-6 (20 ng/ml) treatment. RNA-Seq of hyper-IL-6-stimulated hepatocytes was enriched in genes associated with neutrophil recruitment, and we identified a set of 11 co-clustered genes that characterized a subset of AH patients with enhanced expression of these IL-6TS-inducible transcripts (IL-6TS high). These patients exhibited increased intrahepatic neutrophilic infiltration on liver biopsies and enrichment of pathways associated with leukocyte migration on IPA analysis. In mice, ethanol treatment increased hepatic STAT3 activation despite reduced IL-6R and gp130 expression, and ethanol enhanced expression of neutrophil chemoattractants, includingIcam1,Lbp, andLcn2.Conclusion:Together, these findings suggest that trans IL-6 signaling preserves hepatocyte STAT3-dependent expression of neutrophil chemoattractants in AH. Future studies will examine if inhibiting IL-6 trans signaling abrogates neutrophilic inflammation in AH.
2025-06-01 | GSE255379 | GEO
Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals. PARALLEL study design with 26 samples. Biological replicates: 2 to 3 replicates per group with wild type air exposed animals as controls for each time point (24, 48, 72 hours). Time-Course, Dose-Response, Strain comparison
2011-10-18 | E-GEOD-25095 | biostudies-arrayexpress
Project description:In this study we tested interactions between IL-36 and IL-17A in human keratinocytes. 24 hours of IL-36 stimulation in keratinocytes promoted IL-36, IL-17C, and characteristic psoriasis-related molecule expressions in normal human epidermal keratinocytes in dose-dependent manners as measured by mRNA and protein quantification.
2021-12-31 | GSE160904 | GEO
Project description:IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B or IL-36G. We identified some early IL-1B-specific responses (8 hours post-treatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 hours post-treatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 hours) followed by no response or repression (24 hours). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 + 24 hours). These involved up-regulation of ligands (IL1A, IL1B, IL36G) and activating proteases (CTSS), but also up-regulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, IBD, primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses.
2018-03-04 | GSE109182 | GEO