Nr4a1-Dependent Ly6C ^low Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal

Summary

The functions of Nr4a1-dependent Ly6C ^low monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid “danger” signal, which may signify viral infection or local cell death, triggers Gα i-dependent intravascular retention of Ly6C ^low monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7 -dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C ^low monocyte development, crawling, or retention in Nr4a1 ^−/− , Itgal ^−/−, and Tlr7 ^{host−/−BM+/+} and Cx3cr1 ^−/− mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7 ^{host+/+BM−/−} mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C ^low monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.

Abstract

Graphical Abstract

Highlights

► Ly6C ^low monocytes are accessory cells of the endothelium ► Ly6C ^low monocytes scavenge microparticles and necrotic debris ► Capillaries retain Ly6C ^low monocytes in response to a TLR7 “danger signal” ► Ly6C ^low monocytes recruit neutrophils that mediate necrosis of endothelial cells

Abstract

Nr4a1-dependent Ly6C ^low monocytes scavenge microparticles from the lumenal side of the vascular endothelium and phagocytose cellular debris in response to a TLR7 immune signal, suggesting a role in endothelial surveillance.