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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Elsevier
2025-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001077 |
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| author | Peizhi Tao Beiting Su Xueyan Mao Yusen Lin Li Zheng Xiaoling Zou Hailing Yang Jing Liu Hongtao Li |
| author_facet | Peizhi Tao Beiting Su Xueyan Mao Yusen Lin Li Zheng Xiaoling Zou Hailing Yang Jing Liu Hongtao Li |
| author_sort | Peizhi Tao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e1c49354880f414bb0e8b8a3a3168ae6 |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-e1c49354880f414bb0e8b8a3a3168ae62025-08-20T02:12:03ZengElsevierRedox Biology2213-23172025-05-018210359410.1016/j.redox.2025.103594Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axisPeizhi Tao0Beiting Su1Xueyan Mao2Yusen Lin3Li Zheng4Xiaoling Zou5Hailing Yang6Jing Liu7Hongtao Li8Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaDepartment of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaCorresponding author.; Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaCorresponding author.; Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, People's Republic of ChinaCigarette 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.http://www.sciencedirect.com/science/article/pii/S2213231725001077Interleukin-35Neutrophil extracellular trapsTh17 cellTreg cellCigarette smoke exposed-asthma |
| spellingShingle | Peizhi Tao Beiting Su Xueyan Mao Yusen Lin Li Zheng Xiaoling Zou Hailing Yang Jing Liu Hongtao Li Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis Redox Biology Interleukin-35 Neutrophil extracellular traps Th17 cell Treg cell Cigarette smoke exposed-asthma |
| title | Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis |
| title_full | Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis |
| title_fullStr | Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis |
| title_full_unstemmed | Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis |
| title_short | Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis |
| title_sort | interleukin 35 inhibits nets to ameliorate th17 treg immune imbalance during the exacerbation of cigarette smoke exposed asthma via gp130 stat3 ferroptosis axis |
| topic | Interleukin-35 Neutrophil extracellular traps Th17 cell Treg cell Cigarette smoke exposed-asthma |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725001077 |
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