Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis [scRNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA922146 | ENA |
REPOSITORIES: ENA
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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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Project description:Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis [bulk RNA-Seq]
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Project description:CD39- and CD39+ human thymus-derived regulatory T-cells (tTreg) present as distinct subsets with specific functional and metabolic response patterns. Both cell types express equal levels of the canonical tTreg transcription factors FOXP3 and Helios and overexpression studies have shown that CD39 expression is independent of these two transcription factors. So far, no transcriptomic analyses to adress these differences have been performed. We used microarrays to detail the global programme of gene expression between CD39- and CD39+ human tTreg and identified distinct classes of up-regulated and down-regulated genes between these two subsets.
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Project description:To explore the functional difference between CD90+CD39+ and CD90+CD39- fibroblasts in human hypertrophic scar and normal skin, the gene expresson microarray was performed on Live CD49f- E-Cadherin- Lin- CD45- CD31- CD90+ CD39+ and Live CD49f- E-Cadherin- Lin- CD45- CD31- CD90+ CD39- cells sorted from suspension disgested from three human hypertrophic scar samples; and Live CD49f- E-Cadherin- Lin- CD45- CD31- CD90+ CD39+ cells sorted from suspension disgested from three human normal skin samples
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Project description:Transcriptomes of differentiated cells of the conditionally immortalized mouse podocyte cell line SVI (Schiwek et al., Kidney Int. 66: 91-101, 2004) were determined as described in Warsow et al. (Kidney Int. 84: 104-115, 2013) after application of mechanical stress (Endlich et al., J. Am. Soc. Nephrol. 12: 413-422, 2001) as compared to control conditions. Elevated glomerular pressure represents a high risk for the development of severe kidney diseases and causes an increase of mechanical load to podocytes. In this study we investigated whether mechanical stress alters gene expression in cultured podocytes using gene arrays. We found that tetraspanin CD9 is significantly upregulated in cultured podocytes after mechanical stress. The differential expression of CD9 was confirmed by RT-PCR and Western blot under stretched and unstretched conditions. Furthermore, mechanical stress resulted in a relocalization of CD9. To get an insight into the functional role of CD9, podocytes were transfected with pEGFP-CD9. The expression of CD9 induced the formation of substratum-attached thin arborized protrusions (TAPs). Ca2+ depletion revealed that podocytes over-expressing CD9 possess altered adhesive properties in contrast to the control transfected cells. Finally, elevated CD9 expression increased migration of podocytes in a wound assay. In summary, our results suggest that upregulation of CD9 may play an important role in podocyte morphology, adhesion and migration.
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Project description:Targeting CD39 in cancer - a novel immune mechanism of action.
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Project description:Transcriptomes of differentiated cells of the conditionally immortalized mouse podocyte cell line SVI (Schiwek et al., Kidney Int. 66: 91-101, 2004) were determined as described in Warsow et al. (Kidney Int. 84: 104-115, 2013) after application of mechanical stress (Endlich et al., J. Am. Soc. Nephrol. 12: 413-422, 2001) as compared to control conditions. Elevated glomerular pressure represents a high risk for the development of severe kidney diseases and causes an increase of mechanical load to podocytes. In this study we investigated whether mechanical stress alters gene expression in cultured podocytes using gene arrays. We found that tetraspanin CD9 is significantly upregulated in cultured podocytes after mechanical stress. The differential expression of CD9 was confirmed by RT-PCR and Western blot under stretched and unstretched conditions. Furthermore, mechanical stress resulted in a relocalization of CD9. To get an insight into the functional role of CD9, podocytes were transfected with pEGFP-CD9. The expression of CD9 induced the formation of substratum-attached thin arborized protrusions (TAPs). Ca2+ depletion revealed that podocytes over-expressing CD9 possess altered adhesive properties in contrast to the control transfected cells. Finally, elevated CD9 expression increased migration of podocytes in a wound assay. In summary, our results suggest that upregulation of CD9 may play an important role in podocyte morphology, adhesion and migration. Three independent batches were used.
2015-02-27 | E-GEOD-66336 | biostudies-arrayexpress