Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis
Cigarette smoke (CS) exposure amplifies neutrophil accumulation. IL-35, a novel cytokine with anti-inflammatory properties, is involved in protection against asthma. However, the biological roles of neutrophils and the precise molecular mechanisms of IL-35 in CS exposed-asthma remain unclear. We sho...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001077 |
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| Summary: | Cigarette smoke (CS) exposure amplifies neutrophil accumulation. IL-35, a novel cytokine with anti-inflammatory properties, is involved in protection against asthma. However, the biological roles of neutrophils and the precise molecular mechanisms of IL-35 in CS exposed-asthma remain unclear. We showed that the exacerbation of CS exposed-asthma leads to dramatically increased neutrophil counts and an imbalance in DC-Th17/Treg immune responses. RNA sequencing revealed that NETs, part of a key biological process in neutrophils, were significantly upregulated in the context of CS exposed-asthma exacerbation and that IL-35 treatment downregulated NET-associated gene expression. Targeted degradation of NETs, rather than neutrophil depletion, alleviated the CS exposed-asthma. Mechanistically, STAT3 phosphorylation promoted ferroptosis, exacerbating NET release, which in turn enhanced dendritic cell (DC) antigen presentation, activated T cells, and specifically promoted Th17 cell differentiation while inhibiting Treg cells. IL-35 acting on the gp130 receptor alleviated STAT3-mediated ferroptosis-associated NET formation. In summary, our study revealed a novel mechanism by which IL-35 inhibited NET formation, subsequently alleviating neutrophilic inflammation and restoring the DC-Th17/Treg imbalance in CS exposed-asthma, highlighting the potential of IL-35 as a targeted therapeutic strategy. |
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| ISSN: | 2213-2317 |