The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury.
Chemokines and their receptors such as CCR2 and CX3CR1 mediate leukocyte adhesion and migration into injured tissue. To further define mechanisms of monocyte trafficking during kidney injury we identified two groups of F4/80-positive cells (F4/80(low) and F4/80(high)) in the normal mouse kidney that phenotypically correspond to macrophages and dendritic cells, respectively. Following ischemia and 3 h of reperfusion, there was a large influx of F4/80(low) inflamed monocytes, but not dendritic cells, into the kidney. These monocytes produced TNF-alpha, IL-6, IL-1alpha and IL-12. Ischemic injury induced in CCR2(-/-) mice or in CCR2(+/+) mice, made chimeric with CCR2(-/-) bone marrow, resulted in lower plasma creatinine levels and their kidneys had fewer infiltrated F4/80(low) macrophages compared to control mice. CX3CR1 expression contributed to monocyte recruitment into inflamed kidneys, as ischemic injury in CX3CR1(-/-) mice was reduced, with fewer F4/80(low) macrophages than controls. Monocytes transferred from CCR2(+/+) or CX3CR1(+/-) mice migrated into reperfused kidneys better than monocytes from either CCR2(-/-) or CX3CR1(-/-) mice. Adoptive transfer of monocytes from CCR2(+/+) mice, but not CCR2(-/-) mice, reversed the protective effect in CCR2(-/-) mice following ischemia-reperfusion. Egress of CD11b(+)Ly6C(high) monocytes from blood into inflamed kidneys was CCR2- and CX3CR1-dependent. Our study shows that inflamed monocyte migration, through CCR2- and CX3CR1-dependent mechanisms, plays a critical role in kidney injury following ischemia reperfusion.
Li
Li
L
Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ll3m@virginia.edu
Huang
Liping
L
Sung
Sun-Sang J
SS
Vergis
Amy L
AL
Rosin
Diane L
DL
Rose
C Edward
CE
Lobo
Peter I
PI
Okusa
Mark D
MD
D019264:Adoptive Transfer; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002633:Chemotaxis / Q000276:immunology*; D007511:Ischemia; D007674:Kidney Diseases / Q000276:immunology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology; D054390:Receptors, CCR2 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology*
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine