TY - JOUR
T1 - Nr4a1-Dependent Ly6C(low) Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal
AU - Carlin, Leo M.
AU - Stamatiades, Efstathios G.
AU - Auffray, Cedric
AU - Hanna, Richard N.
AU - Glover, Leanne
AU - Vizcay-Barrena, Gema
AU - Hedrick, Catherine C.
AU - Cook, H. Terence
AU - Diebold, Sandra
AU - Geissmann, Frederic
PY - 2013/4/11
Y1 - 2013/4/11
N2 - 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 Gai-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.
AB - 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 Gai-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.
KW - BONE-MARROW
KW - BACTERIAL-INFECTION
KW - ATHEROSCLEROSIS
KW - NEPHRITIS
KW - MICE
KW - FRACTALKINE EXPRESSION
KW - DENDRITIC CELLS
KW - FUNCTION-ASSOCIATED ANTIGEN-1
KW - RECRUITMENT
KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS
U2 - 10.1016/j.cell.2013.03.010
DO - 10.1016/j.cell.2013.03.010
M3 - Article
SN - 0092-8674
VL - 153
SP - 362
EP - 375
JO - Cell
JF - Cell
IS - 2
ER -