Distinct eosinophil subsets are modulated by agonists of the commensal-metabolite and vitamin B3 receptor GPR109A during allergic-type inflammation

Abstract

Eosinophils are key contributors to allergic pathology, however, increasingly eosinophils are described to have important roles in organ health and immunoregulation. Factors that impact these diverse functions of eosinophils are not understood. Here we show in allergic-type lung inflammation, metabolically distinct populations of eosinophils can be identified based on expression of Siglec-F (Siglec-Fhi and Siglec-Fint). Notably, the lung Siglec-Fhi population was responsive to the commensal microbiome, expressing the short-chain fatty acid receptor GPR109A. Animals deficient in GPR109A displayed augmented eosinophilia during allergy. Moreover, transferred GPR109A-deficient eosinophils released more eosinophil peroxidase than controls. Treatment with butyrate or vitamin B3, both GPR109A ligands, reduced Siglec-Fhi eosinophil frequency and activation, which was associated with apoptosis of Siglec-Fhi eosinophils. These findings identify GPR109A as an unappreciated regulator of glycolytic Siglec-Fhi eosinophils, raising the possibility of depleting pathological eosinophil populations in disease states while sparing those with homeostatic functions.