ORIGINAL RESEARCH article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
This article is part of the Research TopicImmunometabolism in Immunological Tolerance and Regulation: Novel Mechanisms and Clinical InterventionsView all 11 articles
Cigarette Smoke Exposure Triggers Dendritic Cell-Derived Exosome-Mediated Th17 and Treg Polarization through an Autophagy-and Necroptosis-Associated SIRT1-Dependent Mechanism
Provisionally accepted
Dongling Luo1
Jifeng Liu1*Leilei Ya2Chengxuan Ruan3
Siyi Ou4Yiqian Wei1Qingyun Lin1Zhaohong Huang1Kaiwen Nong1- 1The First People’s Hospital of Qinzhou, Qinzhou, China
- 2Liuzhou Municipal Liutie Central Hospital, Liuzhou, China
- 3The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, China
- 4The First People's Hospital of Qinzhou, Qinzhou, China
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Both Th17/Treg cell imbalance and dendritic cells (DCs) play critical roles in chronic obstructive pulmonary disease pathogenesis from cigarette smoke. Previous studies have shown that DC-derived exosomes (DCexos) can polarize CD4+ T cells toward either Th17 or Treg phenotypes. However, the role of SIRT1 in regulating DCexos-mediated immune responses under cigarette smoke extract (CSE) exposure, and its association with autophagy and necroptosis, remains unclear. In this study, we assessed the expression of silent information regulator 2 homolog 1 (SIRT1), autophagy markers (ATG16L1, LC3B, and p62/SQSTM1), and necroptosis markers (ZBP1, RIPK3, MLKL, Caspase-8, and Caspase-3) in DCs following CSE exposure. Additionally, we evaluated the effect of a SIRT1 activator (SRT1720) on CSE-exposed DCexos and its ability to polarize CD4+ T cells toward Th17 and Treg subsets. DCs were generated from bone marrow-derived mononuclear cells isolated from C57BL/6J mice and assigned to three groups: control DCs, CSE-exposed DCs, and SRT1720-treated CSE-exposed DCs. The ability of each group's exosomes to polarize CD4+ T cells was assessed using a mixed lymphocyte reaction (MLR). SIRT1 expression in CSE-exposed DCs decreased in a time-dependent manner (all p < 0.05). Expression of ATG16L1 and p62 was also reduced, while LC3B expression was increased under CSE-exposed (all p < 0.01). Expression of ZBP1, RIPK3, MLKL, Caspase-8, and Caspase-3 was elevated following CSE exposure (all p < 0.01). Th17 cell frequencies were increased in the CSE-exposed DC-derived exosomes/MLR group compared to the controls (p < 0.01), while Treg frequencies were decreased (p < 0.01). Autophagy could be improved and the necroptosis could be reduced in the SRT1720-treated CSE-exposed DCs (all p < 0.01). Additionally, Th17 cell polarization reduced and Treg cell differentiation increased in the SRT1720-treated CSE-exposed DC-derived exosomes/MLR group compared to the CSE-exposed group (all p < 0.01). In conclusion, CSE exposure induces an imbalance in Th17/Treg polarization through a process mediated by DCexos that entails reduced SIRT1 expression, increased necroptosis, and dysregulated autophagy. SIRT1 activation by SRT1720 can attenuate these effects by restoring immune balance and modulating cell death and survival pathways in DCs under CSE exposure.
Keywords: Exosomes, dendritic cell, Cigarette smoke extract, Silent information regulator 2 homolog 1, CD4+ T cells
Received: 29 Sep 2025; Accepted: 29 Nov 2025.
Copyright: © 2025 Luo, Liu, Ya, Ruan, Ou, Wei, Lin, Huang and Nong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jifeng Liu
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