ICOS regulates IL-10 production in group 2 innate lymphoid cells via cholesterol and cortisol biosynthesis
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Mohammad H. Kazemi, Xin Li, Stephen Shen, Omid Akbari
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Mohammad H. Kazemi, Xin Li, Stephen Shen, Omid Akbari
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Research Article Immunology Pulmonology

ICOS regulates IL-10 production in group 2 innate lymphoid cells via cholesterol and cortisol biosynthesis

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 enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated 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

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Figure 5

ICOS controls cholesterol biosynthesis in ILC2s for IL-10 production.

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ICOS controls cholesterol biosynthesis in ILC2s for IL-10 production. (A...
(A) Pulmonary aILC2s were isolated from WT and ICOS-KO mice subjected to i.n. IL-33 challenge for 3 days and cultured. Subsequently, aILC2s were analyzed using Filipin, NBD cholesterol, or BODIPY542/563. (B) Representative histogram of cholesterol quantity assessed with Filipin fluorescent tracer. Corresponding quantitation is presented as MFI. n = 4. (C) Representative histogram of NBD cholesterol uptake assessed with a cholesterol uptake kit. Corresponding quantitation is presented as MFI. n = 4. (D) Representative histogram of lipid utilization assessed with BODIPY542/563. Corresponding percent change in MFI before and after incubation is presented. n = 4. (E–H) WT and ICOS-KO aILC2s were cultured with or without U18666A or statin. (F) Levels of IL-10 in the culture supernatant were measured. n = 4. (G and H) Representative plots of MAF (G) and NFIL3 (H) expression levels in each group are shown. Corresponding quantitation is presented as MFI. n = 4. Data are presented as mean ± SEM and are representative of 4 independent experiments. Two-tailed Student’s t test or 1-way ANOVA followed by Tukey’s post hoc tests was employed for statistical analysis; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Schematic images were created in Adobe Illustrator. FMO, fluorescence minus one.