Nr4a1-Dependent Ly6Clow Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal

Abstract

SummaryThe functions of Nr4a1-dependent Ly6Clow 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 Gαi-dependent intravascular retention of Ly6Clow 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 Ly6Clow monocyte development, crawling, or retention in Nr4a1−/−, Itgal−/−, and Tlr7host−/−BM+/+ and Cx3cr1−/− mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7host+/+BM−/− mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6Clow 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.

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

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Microglia and Monocyte-Derived Macrophages in Stroke

“…CCR2 expression is critical for the trafficking of circulating monocytes into inflamed tissue where they give rise to macrophages. The anti-inflammatory monocytes, which do not express CCR2 but do express higher levels of CX 3 CR1, patrol blood vessels in a steady state, performing in situ phagocytosis [78,81].…”

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

“…Evidence indicates that nonclassical monocytes perform a specialized form of immune homeostasis, serving as initiators of acute inflammatory responses and contributing to tissue remodeling (5,6,13,(17)(18)(19). A unique aspect of the function of these cells is their capacity to undergo extensive intravascular crawling or "patrolling," a constitutive phenomenon that has now been observed in a wide range of organs (5,6,(20)(21)(22). A growing body of evidence indicates that this form of immune surveillance allows Significance Nonclassical monocytes patrol the microvascular lumen in numerous organs in behavior thought to represent a form of immune surveillance.…”

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