BACKGROUND:

Allergic asthma is characterized airway hyperreactivity (AHR) and inflammation driven by aberrant T_H2 response. Type 2 innate lymphoid cells (ILC2s) are a critical source of T_H2 cytokines IL-5 and IL-13 which promote acute asthma exacerbation. Short chain fatty acids (SCFAs) have been shown to attenuate T cell-mediated allergic airway inflammation. Their role in the regulation of ILC2-driven AHR and lung inflammation, however, remains unknown.

OBJECTIVE:

We investigated the immunomodulatory role of SCFAs in the regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.

METHODS:

We assessed the role of SCFAs in regulating the survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.

RESULTS:

We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition as TSA, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, co-treatment of TSA and butyrate did not result in additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.

CONCLUSION:

Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity, and may serve as a potential therapeutic target for asthma.