Abstract
Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhances IL-10 production. The absence of ICOS reprograms ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis, and subsequent Glucocorticoid receptor (GR) activation. This reprogramming regulates MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.
Authors
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Mohammad H. Kazemi, Xin Li, Stephen Shen, Omid Akbari
Graphical abstract
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)