LAUSR

The murine serous cavities contain a rare and enigmatic population of short‐lived F4/80loMHCII+ macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80loMHCII+ 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– F4/80loMHCII+ 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 F4/80loMHCII+ 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.