IL-4R signaling mediated polarization of neutrophils promoted monocytes derived alveolar macrophages function

Abstract

Abstract We have reported that alternatively activated neutrophils (N2) enhance lung anti-helminth trained macrophage effector function in response to infection with N. brasiliensis(Fei Chen, et al., NI, 2014). However, it is not clear how these neutrophils develop and what lung macrophage subsets actually mediate resistance. We report here that IL-4R signaling is required for the polarization of neutrophils within 2 days after N. brasiliensisinfection and that this characteristic N2 phenotype can develop in Rag−/− but not Rag2cg−/− mice, suggesting a role for innate lymphoid cells in initiating N2 cell differentiation. N2 neutrophils further showed significant proliferative capacity and oxidative phosphorylation at day 2 after N. brasiliensisinfection. Using CD45 congenic transfers and fate mapping Cx3cr1creER-YFP/+R26tdTomato/+ mice, we further show that monocyte-derived alveolar macrophages are the major effector macrophage subset mediating parasite killing through Arginase 1 dependent mechanisms. In vivo depletion of neutrophils with anti-Ly6G Ab blocked the development of this anti-helminth pulmonary macrophage subset and RNAseq analyses show marked differences from tissue resident alveolar macrophages. These studies demonstrate heterogeneity in lung macrophage and neutrophil subsets during helminth infection resulting in distinct activation pathways required for helminth resistance.