Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80 hiGATA6 + macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C + monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80 loMHCII + cells that act, in part, as precursors of F4/80 hiGATA6 + macrophages. Notably, monocyte-derived F4/80 hi macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.
Understanding the heterogeneity of peritoneal macrophages is hampered by controversy over their origin and homeostasis. Here the authors show the embryonic F4/80hi population is replaced over time by self-renewing bone marrow-derived cells transitioning from F4/80lo to F4/80hi in adult mice, and that such turnover is more rapid in male mice.