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-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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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
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