Institute for Immunology, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.
State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
J Allergy Clin Immunol. 2022 Jun;149(6):2091-2104. doi: 10.1016/j.jaci.2021.12.783. Epub 2021 Dec 30.
Group 2 innate lymphoid cells (ILC2s), the innate counterpart of T2 cells, play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear.
The aim of this study was to explore the importance of signal transducer and activator of transcription 3 (STAT3) to ILC2 function in allergic lung inflammation.
Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in VavStat3, Il5Stat3, and RorcStat3 mice to verify the necessity of functional STAT3 for ILC2 allergic response. The intrinsic role of STAT3 in regulating ILC2 function was examined by generation of bone marrow chimera mice. The underlying mechanism was studied through confocal imaging, metabolomics analysis, and chromatin immunoprecipitation quantitative PCR.
STAT3 is essential for ILC2 effector function and promotes ILC2-driven allergic inflammation in the lung. Mechanistically, the alarmin cytokine IL-33 induces a noncanonical STAT3 phosphorylation at serine 727 in ILC2s, leading to translocation of STAT3 into the mitochondria. Mitochondrial STAT3 further facilitates adenosine triphosphate synthesis to fuel the methionine cycle and generation of S-adenosylmethionine, which supports the epigenetic reprogramming of type 2 cytokines in ILC2s. STAT3 deficiency, inhibition of STAT3 mitochondrial translocation, or blockade of methionine metabolism markedly dampened the ILC2 allergic response and ameliorated allergic lung inflammation.
The mitochondrial STAT3-methionine metabolism pathway is a key regulator that shapes ILC2 effector function through epigenetic regulation, and the related proteins or metabolites represent potential therapeutic targets for allergic lung inflammation.
2 型固有淋巴细胞（ILC2）是 T2 细胞的固有对应物，在 2 型免疫反应中发挥关键作用。然而，ILC2 的分子调控机制尚不清楚。
本研究旨在探讨信号转导和转录激活因子 3（STAT3）对 ILC2 在变应性肺炎症中的功能的重要性。
通过鼻内给予蛋白酶过敏原木瓜蛋白酶在 VavStat3、Il5Stat3 和 RorcStat3 小鼠中建立急性和慢性哮喘模型，以验证功能性 STAT3 对 ILC2 变应性反应的必要性。通过生成骨髓嵌合体小鼠来检查 STAT3 在调节 ILC2 功能中的内在作用。通过共聚焦成像、代谢组学分析和染色质免疫沉淀定量 PCR 研究潜在机制。
STAT3 是 ILC2 效应功能所必需的，并促进 ILC2 在肺部驱动的变应性炎症。机制上，警报素细胞因子 IL-33 在 ILC2 中诱导非经典 STAT3 丝氨酸 727 磷酸化，导致 STAT3 易位到线粒体。线粒体 STAT3 进一步促进三磷酸腺苷合成，为甲硫氨酸循环和 S-腺苷甲硫氨酸的产生提供燃料，从而支持 ILC2 中 2 型细胞因子的表观遗传重编程。STAT3 缺陷、STAT3 线粒体易位抑制或阻断蛋氨酸代谢显著抑制 ILC2 变应性反应并改善变应性肺炎症。
线粒体 STAT3-蛋氨酸代谢途径是通过表观遗传调节塑造 ILC2 效应功能的关键调节剂，相关蛋白或代谢物代表变应性肺炎症的潜在治疗靶点。
