Regulation of type 2 innate lymphoid cell–dependent airway hyperreactivity by butyrate

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Christina Li-Ping Thio, Po-Yu Chi, Alan Chuan-Ying Lai, Ya-Jen Chang

Background

Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant T_H2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the 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. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.

Objective

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

Methods

We assessed the role of SCFAs in regulating 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 the 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, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an 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 can serve as a potential therapeutic target for asthma.

Graphical abstract

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