CSF1R regulates monocyte subset differentiation and intracellular metabolism

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6C ^high ) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6C ^low ) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6C ^low monocytes in part by blunting differentiation of Ly6C ^high monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.