Researchers from the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), have revealed a novel mechanism by which the chromatin remodeling factor Brg1 exacerbates allergic lung inflammation by regulating the chromatin status of Group 2 innate lymphoid cells (ILC2s), enhancing their aerobic glycolytic metabolism, and consequently promoting the expansion of effector ILC2s (ILC2eff) and memory ILC2s (ILC2mem). Their findings entitled "Brg1-imprinted chromatin status controls the effector and memory group 2 innate lymphoid cell metabolism to exacerbate allergic lung inflammation" were published in the Journal of Allergy and Clinical Immunology on Sept. 17, 2025.

Asthma is a highly prevalent chronic respiratory disease worldwide, closely associated with the over-activation of type 2 immunity. The core pathological features include airway hyper-responsiveness, eosinophil infiltration and excessive mucus secretion, which significantly impact patients' quality of life and can even be life-threatening. Previous research has long indicated that helper T cell 2 (Th2 cells) are key immune cells driving asthma. However, recent studies have identified a type of innate immune cell named "ILC2s" that also plays a central role. Unlike Th2 cells, ILC2s do not require antigen activation and can rapidly respond to environmental stimuli (such as allergens like pollen, dust mites, and proteases), secreting inflammatory cytokines like IL-5 and IL-13 to directly induce airway inflammation.

More importantly, recent studies have shown that ILC2s also possess "trained immunity" or “innate immune memory” characteristics. After initial exposure to an allergen, ILC2s can be in a "memory" state. Upon re-exposure to low doses of the allergen or inflammatory signals (such as IL-33), they rapidly activate and proliferate extensively, triggering a more intense "secondary inflammation". This is a crucial reason for the recurrent nature and difficulty in cure of asthma. However, the underlying epigenetic regulatory mechanisms governing how ILC2s form and maintain this memory capacity remain unclear.

To investigate this issue, researchers first conducted multi-omics analyses and found that the expression of Brg1 (encoded by Smarca4), a core component of the chromatin remodeling complex mSWI/SNF, was significantly upregulated in a mouse model of allergic lung inflammation. The inflammatory cytokine IL-33, a key signal inducing ILC2 activation in asthma, directly induced Brg1 expression in ILC2s, suggesting Brg1 might be a "key switch" for ILC2 activation.

Further experiments demonstrated that during ILC2 activation, Brg1 binds to and opens a series of chromatin regions, particularly gene loci related to cellular metabolism. Notably, Brg1 promotes the glycolytic process in ILC2s by enhancing the chromatin accessibility of key metabolic genes such as Hif1a and Ldha, thereby supporting their expansion and survival.

The researchers also discovered that this "metabolic imprint" shaped by Brg1 can be retained from effector ILC2s to memory ILC2s, enabling memory cells to maintain high levels of glycolytic activity and rapid response capability upon re-exposure to allergens. In animal models, specific knockout of the Smarca4 or Hif1a in ILC2s significantly inhibited ILC2 proliferation and alleviated both acute and secondary lung inflammation, demonstrating that Hif1α is a key molecule connecting Brg1 to the memory characteristics of ILC2s.

Regarding clinical practice, researchers further intervened using the small molecule Brg1 inhibitor Compound 14. They found that this inhibitor not only effectively alleviated allergic lung inflammation in mice but also demonstrated superior efficacy compared to traditional steroids (dexamethasone) in suppressing the ILC2 memory response. These findings suggest that targeting Brg1 could represent a potential new strategy for treating asthma and other allergic diseases.

This study has revealed the epigenetic mechanism of how Brg1 imprints ILC2 effector and memory responses to exacerbate the primary and recurrent asthma. The findings not only deepens the understanding of asthma pathogenesis but also provides new insights into developing novel therapies targeting innate immune memory.

Dr. TANG Jupeifrom SINH and Dr. SUN Hanxiao from Tongren Hospital, Shanghai Jiao Tong University School of Medicine are the first authors. Dr. QIU Ju, Dr. QIN Jun and Dr. QIU Jinxin from SINH are the corresponding authors of this article. This research received kind help and support from Drs. SU Xiao , ZOU Qiang , SHENG Huiming , ZHOU Hong , GUO Xiaohuan , SHEN Lei, LI Shiyang, SHAO Zhen and YANG Lifeng.

The study was sponsored by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.

Brg1-imprinted chromatin status controls the effector and memory group 2 innate lymphoid cell metabolism to exacerbate allergic lung inflammation. (Image provided by Dr. QIU Ju’s group)

Paper link: https://doi.org/10.1016/j.jaci.2025.08.029

Scientific Contact:
Prof. QIU Ju
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: qiuju@sinh.ac.cn 

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn