巨噬细胞SIRT6通过ATG3去乙酰化介导的自噬促进过敏性气道炎症
2026/04/02
摘要
慢性气道炎症是哮喘发病机制的核心驱动因素，其中巨噬细胞起着关键作用。虽然已知自噬可调节巨噬细胞功能，但将自噬与过敏性气道炎症联系起来的具体分子机制仍不清楚。在此，我们确定巨噬细胞沉默调节蛋白6（SIRT6）是哮喘中自噬和过敏性炎症的关键调节因子。哮喘小鼠的肺组织和巨噬细胞中SIRT6表达升高。髓系特异性SIRT6缺失可减轻哮喘小鼠模型中的过敏性气道炎症。从机制上讲，SIRT6通过巨噬细胞中自噬相关蛋白3（ATG3）介导的自噬促进促炎细胞因子的表达。我们进一步证明，SIRT6直接与ATG3结合并使其第77位赖氨酸（K77）去乙酰化，这种修饰是驱动促炎反应所必需的。重要的是，用OSS_128167对SIRT6进行药理学抑制可抑制巨噬细胞自噬并减轻过敏性炎症。我们的研究结果表明，SIRT6通过使巨噬细胞中的ATG3去乙酰化并增强自噬，成为过敏性气道炎症的关键促进因子，凸显了抑制SIRT6作为哮喘潜在新治疗策略的可能性。
Macrophage SIRT6 promotes allergic airway inflammation through ATG3 deacetylation-mediated autophagy
Yuting Lei, Zhilin Xiong, Mengting Zhang, Shihai Li, Guomei Su, Ruina Huang, Jielin Duan, Xiao Gao, Tianwen Lai
Abstract
Chronic airway inflammation is a central driver of asthma pathogenesis, in which macrophages play a pivotal role. While autophagy is known to regulate macrophage function, the specific molecular mechanisms linking autophagy to allergic airway inflammation remain unclear. Here, we identify macrophage sirtuin 6 (SIRT6) as a critical regulator of autophagy and allergic inflammation in asthma. SIRT6 expression was elevated in lung tissues and macrophages from asthmatic mice. Myeloid-specific Sirt6 deletion attenuated allergic airway inflammation in asthma murine model. Mechanistically, SIRT6 promoted proinflammatory cytokine expression via autophagy-related 3 (ATG3)-mediated autophagy in macrophages. We further demonstrated that SIRT6 directly bound to ATG3 and deacetylated it at lysine 77 (K77), a modification required for driving the proinflammatory response. Importantly, pharmacological inhibition of SIRT6 with OSS_128167 suppressed macrophage autophagy and alleviated allergic inflammation. Our findings establish SIRT6 as a key promoter of allergic airway inflammation through ATG3 deacetylation and enhanced autophagy in macrophages, highlighting SIRT6 inhibition as a potential novel therapeutic strategy for asthma.
慢性气道炎症是哮喘发病机制的核心驱动因素，其中巨噬细胞起着关键作用。虽然已知自噬可调节巨噬细胞功能，但将自噬与过敏性气道炎症联系起来的具体分子机制仍不清楚。在此，我们确定巨噬细胞沉默调节蛋白6（SIRT6）是哮喘中自噬和过敏性炎症的关键调节因子。哮喘小鼠的肺组织和巨噬细胞中SIRT6表达升高。髓系特异性SIRT6缺失可减轻哮喘小鼠模型中的过敏性气道炎症。从机制上讲，SIRT6通过巨噬细胞中自噬相关蛋白3（ATG3）介导的自噬促进促炎细胞因子的表达。我们进一步证明，SIRT6直接与ATG3结合并使其第77位赖氨酸（K77）去乙酰化，这种修饰是驱动促炎反应所必需的。重要的是，用OSS_128167对SIRT6进行药理学抑制可抑制巨噬细胞自噬并减轻过敏性炎症。我们的研究结果表明，SIRT6通过使巨噬细胞中的ATG3去乙酰化并增强自噬，成为过敏性气道炎症的关键促进因子，凸显了抑制SIRT6作为哮喘潜在新治疗策略的可能性。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Mucosal Immunol. 2026 Mar 19:S1933-0219(26)00033-4. doi: 10.1016/j.mucimm.2026.03.009. ）
（Mucosal Immunol. 2026 Mar 19:S1933-0219(26)00033-4. doi: 10.1016/j.mucimm.2026.03.009. ）
Macrophage SIRT6 promotes allergic airway inflammation through ATG3 deacetylation-mediated autophagy
Yuting Lei, Zhilin Xiong, Mengting Zhang, Shihai Li, Guomei Su, Ruina Huang, Jielin Duan, Xiao Gao, Tianwen Lai
Abstract
Chronic airway inflammation is a central driver of asthma pathogenesis, in which macrophages play a pivotal role. While autophagy is known to regulate macrophage function, the specific molecular mechanisms linking autophagy to allergic airway inflammation remain unclear. Here, we identify macrophage sirtuin 6 (SIRT6) as a critical regulator of autophagy and allergic inflammation in asthma. SIRT6 expression was elevated in lung tissues and macrophages from asthmatic mice. Myeloid-specific Sirt6 deletion attenuated allergic airway inflammation in asthma murine model. Mechanistically, SIRT6 promoted proinflammatory cytokine expression via autophagy-related 3 (ATG3)-mediated autophagy in macrophages. We further demonstrated that SIRT6 directly bound to ATG3 and deacetylated it at lysine 77 (K77), a modification required for driving the proinflammatory response. Importantly, pharmacological inhibition of SIRT6 with OSS_128167 suppressed macrophage autophagy and alleviated allergic inflammation. Our findings establish SIRT6 as a key promoter of allergic airway inflammation through ATG3 deacetylation and enhanced autophagy in macrophages, highlighting SIRT6 inhibition as a potential novel therapeutic strategy for asthma.
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