A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation

Liuhui Fu; Jie Zhao; Jiaoyan Huang; Na Li; Xin Dong; Yao He; Wenyan Wang; Yu Wang; Ju Qiu; Xiaohuan Guo

doi:10.1016/j.jaci.2021.12.783

A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation

J Allergy Clin Immunol. 2022 Jun;149(6):2091-2104. doi: 10.1016/j.jaci.2021.12.783. Epub 2021 Dec 30.

Authors

Liuhui Fu¹, Jie Zhao¹, Jiaoyan Huang¹, Na Li¹, Xin Dong¹, Yao He¹, Wenyan Wang¹, Yu Wang², Ju Qiu³, Xiaohuan Guo⁴

Affiliations

¹ 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.
² State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
³ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
⁴ 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. Electronic address: guoxiaohuan@tsinghua.edu.cn.

PMID: 34974065
DOI: 10.1016/j.jaci.2021.12.783

Abstract

Background: Group 2 innate lymphoid cells (ILC2s), the innate counterpart of T_H2 cells, play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear.

Objective: 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.

Methods: Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in Vav^icreStat3^fl/fl, Il5^tdtomato-creStat3^fl/fl, and Rorc^creStat3^fl/fl 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.

Results: 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.

Conclusion: 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.

Keywords: Allergic lung inflammation; ILC2; STAT3; histone methylation; methionine metabolism; mitochondria.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alveolitis, Extrinsic Allergic*
Animals
Cytokines
Epigenesis, Genetic
Hypersensitivity*
Immunity, Innate
Interleukin-33
Lung
Lymphocytes
Methionine
Mice
Mitochondria
Pneumonia*
Pulmonary Eosinophilia*
STAT3 Transcription Factor

Substances

Cytokines
Interleukin-33
STAT3 Transcription Factor
Stat3 protein, mouse
Methionine