1. Academic Validation
  2. Brg1-imprinted chromatin status controls effector and memory group 2 innate lymphoid cell metabolism to exacerbate allergic lung inflammation

Brg1-imprinted chromatin status controls effector and memory group 2 innate lymphoid cell metabolism to exacerbate allergic lung inflammation

  • J Allergy Clin Immunol. 2025 Sep 17:S0091-6749(25)00948-0. doi: 10.1016/j.jaci.2025.08.029.
Jupei Tang 1 Hanxiao Sun 2 Huidan Chang 3 Liyun Yuan 3 Yue Chen 1 Xueliang Zhang 4 Yongzhen Tao 1 Lifeng Yang 1 Zhen Shao 1 Xiaohuan Guo 5 Hong Zhou 6 Huiming Sheng 2 Qiang Zou 7 Xiao Su 8 Jinxin Qiu 9 Jun Qin 10 Ju Qiu 11
Affiliations

Affiliations

  • 1 Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Rheumatology and Immunology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.
  • 6 School of Life Science, Anhui Medical University, Hefei, China.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Unit of Respiratory Immunity and Infection, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 9 Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: jxqiu@sinh.ac.cn.
  • 10 Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: qinjun@sinh.ac.cn.
  • 11 Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: qiuju@sinh.ac.cn.
Abstract

Background: The chromatin status fluctuates with effector and memory group 2 innate lymphoid cell (ILC2) responses. How this intricate coordination affects allergic lung inflammation remains unclear.

Objective: We examined how the chromatin remodeler brahma-related gene 1 (Brg1) regulates ILC2s in allergic lung inflammation.

Methods: Acute lung allergic inflammation was induced with papain in wild-type, Il5Cre/+Smarca4flox/flox (Smarca4f/f), Il5Cre/+Hif1af/f, and Il5Cre/+Ldhaf/f mice. Secondary lung inflammation was induced with low-dose IL-33 in papain-primed Il5Cre/+Smarca4f/f mice. ATAC-Seq, RNA Sequencing, and Brg1 CUT&Tag analyses were performed on naive ILC2s, effector ILC2s (ILC2eff), memory ILC2s (ILC2mem), IL-33-challenged Brg1-deficient ILC2s, Brg1-deficient ILC2mem, and human ILC2s treated with or without the Brg1 inhibitor Compound 14. ILC2 metabolism was analyzed by 13C glucose isotype tracing and metabolic flux, Seahorse, and SCENITH assays. Compound 14 was used to treat mouse and humanized mouse models of allergic lung inflammation.

Results: Brg1 expression was upregulated in asthma patients' ILC2s and was induced by IL-33. Brg1 promoted IL-5+ and IL-13+ ILC2 expansion and exacerbated both acute and secondary lung inflammation. Brg1 imprinted the chromatin landscape favoring aerobic glycolysis, the metabolic process reinforced in ILC2eff and ILC2mem. Brg1-augmented Hif1a enhancer accessibility was a sustained epigenetic signature in ILC2mem inherited from ILC2eff, and Hif1α enhanced ILC2eff and ILC2mem responses. Pharmacologic inhibition of Brg1, rather than dexamethasone treatment, in acute phase alleviated secondary lung inflammation.

Conclusion: Brg1 promotes the expansion of pathogenic ILC2eff and ILC2mem and exacerbates allergic lung inflammation. Mechanistically, Brg1 increases the chromatin accessibility and transcription of Hif1a and Ldha, key factors reinforcing ILC2 glycolysis metabolism.

Keywords

Brg1; Group 2 innate lymphoid cell (ILC2); ILC2 memory; allergic lung inflammation; chromatin accessibility; glycolysis.

Figures
Products