自噬在肺巨噬细胞和树突状细胞中发挥作用，以调节变应原依赖性炎症反应
2026/06/01
摘要
哮喘影响着全球2.6亿人，其中与TH17和TH1反应以及以中性粒细胞为主的炎症相关的重症哮喘病例，由于对皮质类固醇不敏感而最难治疗。ATG5基因中的单核苷酸多态性与患重症哮喘的较高风险相关，该基因编码细胞大自噬/自噬循环过程所需的一种蛋白质。我们探究了ATG5变异体与重症哮喘遗传关联的机制基础。我们发现，在屋尘螨（HDM）攻击的小鼠（一种因HDM被残留脂多糖污染而导致的以TH17和TH1为主导的过敏性气道炎症模型）中，ATG5在肺巨噬细胞和树突状细胞（DC）中发挥自噬依赖性作用，以抑制TH17反应和中性粒细胞积聚。相反，在以TH2为主导的卵清蛋白过敏性气道炎症模型中，自噬是促进嗜酸性粒细胞积聚所必需的，这支持了一个模型，即自噬在肺巨噬细胞和DC中以过敏原依赖性方式发挥作用，抑制TH17反应并促进TH2反应。此外，我们发现，暴露于HDM的巨噬细胞也需要自噬来抑制细胞因子和趋化因子的分泌，否则这些物质会将中性粒细胞募集到肺部，且这一过程与T细胞反应无关。总之，我们的数据揭示了先天性免疫细胞中的自噬以T细胞依赖性和非依赖性方式抑制与重症哮喘相关的肺部中性粒细胞积聚。
Autophagy functions in lung macrophages and dendritic cells to regulate allergen-dependent inflammatory responses
Neha Dubey, Reilly Woodson, Skyler V Hendrix, Anne L Rosen, Rachel L Kinsella, Samuel R McKee, Marick Starick, Nicole Rivera-Espinal, Sumanta K Naik, Asya Smirnov, Darren Kreamalmeyer, Andrew L Kau, Christina L Stallings
Abstract
Asthma affects 260 million people worldwide, with severe asthma cases that are associated with TH17 and TH1 responses and neutrophil-dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the ATG5 gene, which codes for a protein required for the cellular recycling process of macroautophagy/autophagy, are associated with higher risk for developing severe asthma. We explored the mechanistic basis for the genetic association of ATG5 variants with severe asthma. We identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing TH17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a TH17- and TH1-dominated model for allergic airway inflammation due to contamination of the HDM with residual lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the TH2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress TH17 responses and promote TH2 responses in an allergen-dependent manner. In addition, we discover that autophagy is also required in macrophages exposed to HDM to suppress the secretion of cytokines and chemokines that would otherwise recruit neutrophils to the lungs, independent of T cell responses. Together, our data identify T-cell-dependent and -independent ways autophagy in innate immune cells suppresses the neutrophil accumulation in lungs that is associated with severe asthma. Abbreviations: AHR: airway hyperresponsiveness; BAL: bronchoalveolar lavages; BMDM: bone marrow-derived macrophages; CSF3/G-CSF: colony stimulating factor 3; DCs: dendritic cells; H&E: hematoxylin and eosin; HDM: house dust mites; i.n.: intranasal/intranasally; i.p.: intraperitoneal/intraperitoneally; Jax: The Jackson Laboratory; KC: keratinocyte-derived chemokine; LPS: lipopolysaccharide; MHC: major histocompatibility complex; OVA: ovalbumin; PAMPs: pathogen-associated molecular patterns; PAS: periodic acid-Schiff; SNP: single-nucleotide polymorphism.
哮喘影响着全球2.6亿人，其中与TH17和TH1反应以及以中性粒细胞为主的炎症相关的重症哮喘病例，由于对皮质类固醇不敏感而最难治疗。ATG5基因中的单核苷酸多态性与患重症哮喘的较高风险相关，该基因编码细胞大自噬/自噬循环过程所需的一种蛋白质。我们探究了ATG5变异体与重症哮喘遗传关联的机制基础。我们发现，在屋尘螨（HDM）攻击的小鼠（一种因HDM被残留脂多糖污染而导致的以TH17和TH1为主导的过敏性气道炎症模型）中，ATG5在肺巨噬细胞和树突状细胞（DC）中发挥自噬依赖性作用，以抑制TH17反应和中性粒细胞积聚。相反，在以TH2为主导的卵清蛋白过敏性气道炎症模型中，自噬是促进嗜酸性粒细胞积聚所必需的，这支持了一个模型，即自噬在肺巨噬细胞和DC中以过敏原依赖性方式发挥作用，抑制TH17反应并促进TH2反应。此外，我们发现，暴露于HDM的巨噬细胞也需要自噬来抑制细胞因子和趋化因子的分泌，否则这些物质会将中性粒细胞募集到肺部，且这一过程与T细胞反应无关。总之，我们的数据揭示了先天性免疫细胞中的自噬以T细胞依赖性和非依赖性方式抑制与重症哮喘相关的肺部中性粒细胞积聚。
（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）
（Autophagy. 2026 May 19:1-18. doi: 10.1080/15548627.2026.2668861.）
（Autophagy. 2026 May 19:1-18. doi: 10.1080/15548627.2026.2668861.）
Autophagy functions in lung macrophages and dendritic cells to regulate allergen-dependent inflammatory responses
Neha Dubey, Reilly Woodson, Skyler V Hendrix, Anne L Rosen, Rachel L Kinsella, Samuel R McKee, Marick Starick, Nicole Rivera-Espinal, Sumanta K Naik, Asya Smirnov, Darren Kreamalmeyer, Andrew L Kau, Christina L Stallings
Abstract
Asthma affects 260 million people worldwide, with severe asthma cases that are associated with TH17 and TH1 responses and neutrophil-dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the ATG5 gene, which codes for a protein required for the cellular recycling process of macroautophagy/autophagy, are associated with higher risk for developing severe asthma. We explored the mechanistic basis for the genetic association of ATG5 variants with severe asthma. We identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing TH17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a TH17- and TH1-dominated model for allergic airway inflammation due to contamination of the HDM with residual lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the TH2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress TH17 responses and promote TH2 responses in an allergen-dependent manner. In addition, we discover that autophagy is also required in macrophages exposed to HDM to suppress the secretion of cytokines and chemokines that would otherwise recruit neutrophils to the lungs, independent of T cell responses. Together, our data identify T-cell-dependent and -independent ways autophagy in innate immune cells suppresses the neutrophil accumulation in lungs that is associated with severe asthma. Abbreviations: AHR: airway hyperresponsiveness; BAL: bronchoalveolar lavages; BMDM: bone marrow-derived macrophages; CSF3/G-CSF: colony stimulating factor 3; DCs: dendritic cells; H&E: hematoxylin and eosin; HDM: house dust mites; i.n.: intranasal/intranasally; i.p.: intraperitoneal/intraperitoneally; Jax: The Jackson Laboratory; KC: keratinocyte-derived chemokine; LPS: lipopolysaccharide; MHC: major histocompatibility complex; OVA: ovalbumin; PAMPs: pathogen-associated molecular patterns; PAS: periodic acid-Schiff; SNP: single-nucleotide polymorphism.
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局部施用多粘菌素B偶联的黏蛋白阿克曼菌外膜囊泡可通过抑制M2巨噬细胞极化来减轻哮喘
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哮喘患者与对照者的气道微生物组多样性、粘膜内细菌及空间免疫
