Researchers have revealed a novel mechanism by which the chromatin remodeler brahma-related gene 1 (Brg1) regulate Group 2 innate lymphoid cells (ILC2s) in allergic lung inflammation. Brg1 exacerbates allergic lung inflammation by regulating the chromatin status of ILC2s, enhancing their aerobic glycolytic metabolism, and consequently promoting the expansion of effector ILC2s (ILC2eff) and memory ILC2s (ILC2mem).

This study, led by Drs. QIU Ju, QIN Jun and QIU Jinxin from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, was published in the Journal of Allergy and Clinical Immunology on Sept. 17.

Asthma is a chronic respiratory disease worldwide driven by over-activation of type 2 immunity. A type of innate immune cell named "ILC2s" plays a central rolein this process, responding rapidly to environmental stimuli and directly inducing airway inflammation. After initial allergen exposure, ILC2s can enter 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 why asthma is recurrent and difficult to cure. However, the underlying epigenetic regulatory mechanisms governing this memory capacity remain unclear.

Through multi-omics analyses, the researchers 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, the 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 by which Brg1 imprints ILC2 effector and memory responses to exacerbate the primary and recurrent asthma. These findings not only deepen our understanding of asthma pathogenesis but also provides new insights into developing novel therapies targeting innate immune memory.

The study was supported 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.