Caillot, Z. | bioRxiv Science

bioRxiv2025

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 (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) 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 Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh 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.

immunology↗

bioRxiv2024

CD226+ adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their origin impacts their functions. We previously observed robust recruitment of monocytes to brown adipose tissue in which they could differentiation into two distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226high macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226high macrophages. We found that MDP-derived CD226high macrophages were also present in other tissues including peritoneal cavity, adrenal glands and all adipose depots. CD226high macrophages were regulated by both GM-CSF and CSF1R. Genetic depletion of CD226high macrophages caused increased BAT and plasma triglyceride content. We thus identify CD226high MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

immunology↗