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

By Leo M. Carlin, Efstathios G. Stamatiades, C. Auffray, R. Hanna, Leanne Glover, G. Vizcay‐Barrena, C. Hedrick, H. Cook, S. Diebold, F. Geissmann. Cell, 2013

698 citations recorded by the source corpus.

Summary The 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.

Subfields: Cell Biology, Cellular and Molecular Neuroscience, Immunology

View Paper: https://www.semanticscholar.org/paper/92ba509c31c2aceb0268b679bc54c282e9c7c1ed

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Citations in the corpus

• Developmental and Functional Heterogeneity of Monocytes. (2018, background): “However, this does not exclude that some cells in the non-classical monocyte pool might develop without passing through a classical monocyte stage (Carlin et al., 2013).”
• From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation (2014, background): “They are able to induce the intravascular recruitment of neutrophils, which trigger endothelial necrosis, and subsequently they clear the resulting debris (51).”
• Macrophage heterogeneity in tissues: phenotypic diversity and functions (2014, background): “Monocytes can interact directly with endothelia to perform poorly defined housekeeping functions (60) or, upon activation, enter tissues at local sites of injury, inflammation, and infection.”
• Origin and Functions of Tissue Macrophages (2014, background): “Patrolling, nonclassical monocytes have a key role in clearing damaged endothelial cells, thereby maintaining integrity of the vasculature (Carlin et al., 2013).”
• Macrophages: development and tissue specialization. (2015, background): “In line with this view, the prime function of Ly6Clow cells seems to be the intravascular survey of endothelial integrity (68, 69) rather than the extravasation and engraftment of tissue.”