Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contribute to tissue integrity as well as to innate and adaptive immune defense. Emerging evidence for labor division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organization of this cellular network are not well defined. Here we report a fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX3CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cells and lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that short-lived Ly6C+ monocytes constitute obligatory steady-state precursors of blood-resident Ly6C- cells and that the abundance of Ly6C+ blood monocytes dynamically controls the circulation lifespan of their progeny.
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We would like to thank R. Haffner for guidance with the ES cell work and the staff of the Weizmann Animal facility for the excellent care. S.Y. was a recipient of a long-term FEBS fellowship; A.M. was a fellow of the Minerva foundation. This work was supported by the Leir Charitable Foundation, the Wolfson Family Charitable Trust, the Israel Science Foundation (ISF), and the Deutsche Forschungsgemeinschaft (DFG) Research Unit (FOR) 1336. S.J. is a Helmsley Scholar at the Crohn’s & Colitis Foundation.