CX3CL1-CX3CR1 Interaction Increases the Population of Ly6C(-)CX3CR1(hi) Macrophages Contributing to Unilateral Ureteral Obstruction-Induced Fibrosis.

ABSTRACT

Chemokines modulate inflammatory responses that are prerequisites for kidney injury. The specific role of monocyte-associated CX3CR1 and its cognate ligand CX3CL1 in unilateral ureteral obstruction (UUO)-induced kidney injury remains unclear. In this study, we found that UUO caused a CCR2-dependent increase in numbers of Ly6C(hi) monocytes both in the blood and kidneys and of Ly6C(-)CX3CR1(+) macrophages in the obstructed kidneys of mice. Using CX3CR1(gfp/+) knockin mice, we observed a rapid conversion of infiltrating proinflammatory Ly6C(+)CX3CR1(1o) monocytes/macrophages to anti-inflammatory Ly6C(-)CX3CR1(hi) macrophages. CX3CR1 deficiency affected neither monocyte trafficking nor macrophage differentiation in vivo upon renal obstruction, but CX3CR1 expression in monocytes and macrophages was required for increases in fibrosis in the obstructed kidneys. Mechanistically, CX3CL1-CX3CR1 interaction increases Ly6C(-)CX3CR1(hi) macrophage survival within the obstructed kidneys. Therefore, CX3CL1 and CX3CR1 may represent attractive therapeutic targets in obstructive nephropathy.