CD11c identifies microbiota and EGR2-dependent MHCII⁺ serous cavity macrophages with sexually dimorphic fate in mice

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.