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

Publication date: Available online 6 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Christina Li-Ping Thio, Po-Yu Chi, Alan Chuan-Ying Lai, Ya-Jen Chang
BackgroundAllergic asthma is characterized airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 response. Type 2 innate lymphoid cells (ILC2s) are a critical source of TH2 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.ObjectiveWe investigated the immunomodulatory role of SCFAs in the regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.MethodsWe 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.ResultsWe 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.ConclusionOur 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.

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