Th17 signaling in asthma: relevance for psychopathology and neuroinflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA757633 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15607100.fastq.gz | Fastqsanger.gz | |||
| SRR15607101.fastq.gz | Fastqsanger.gz | |||
| SRR15607102.fastq.gz | Fastqsanger.gz | |||
| SRR15607103.fastq.gz | Fastqsanger.gz | |||
| SRR15607104.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: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:In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and non-pathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis (EAE), an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase (ALK)4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances anti-inflammatory gene modules. Whole genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other anti-inflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1 and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a novel critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.
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Project description:Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 ug) was administered into the lateral ventricle of mice and, 24 hours later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation. Mice were given intracerebroventricular injections of saline vehicle (n = 4) or lipopolysaccharide (n = 4). Twenty-four hours later, we dissected the hippocampus and cerebral cortex and processed the tissue for microarray analysis. Gene expression changes observed in the microaray data were validated with quantitative real-time PCR.
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Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
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