CD11c identifies microbiota and EGR2‐dependent MHCII<sup>+</sup> serous cavity macrophages with sexually dimorphic fate in mice
Calum C. Bain, Pieter A. Louwe, Nicholas J. Steers, Alberto Bravo‐Blas, Lizi M. Hegarty, Clare Pridans, Simon Milling, Andrew S. MacDonald, Dominik Rückerl, Stephen J. Jenkins
Abstract
Abstract The murine serous cavities contain a rare and enigmatic population of short‐lived F4/80 lo MHCII + macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80 lo MHCII + peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c + cells that express the immunoregulatory cytokine RELM‐α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM‐α, a signature marker shared by CD11c + and CD11c – F4/80 lo MHCII + cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex‐specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80 lo MHCII + macrophages that is regulated by microbiota, and describe a novel sex and site‐specific function for RELM‐α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte‐derived macrophages by the female peritoneal environment.