CX3CL1–CX3CR1 Interaction Increases the Population of Ly6C−CX3CR1hi 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 Ly6Chi monocytes both in the blood and kidneys and of Ly6C−CX3CR1+ macrophages in the obstructed kidneys of mice. Using CX3CR1gfp/+ knockin mice, we observed a rapid conversion of infiltrating proinflammatory Ly6C+CX3CR11o monocytes/macrophages to anti-inflammatory Ly6C−CX3CR1hi 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−CX3CR1hi macrophage survival within the obstructed kidneys. Therefore, CX3CL1 and CX3CR1 may represent attractive therapeutic targets in obstructive nephropathy.

Progression of chronic kidney disease: too much cellular talk causes damage

“…The chemokine fractalkine (CX3CL1) and its CX3CR1 receptor provide another example whereby injured epithelia qualitatively alter the inflammatory infiltrate. The interaction between fractalkine, expressed on injured epithelia, and CX3CR1, expressed on macrophages/DCs, not only directs macrophage recruitment and adhesion, but also increases the survival specifically of pro-fibrotic macrophages (Ly6C − CX3CR1 hi )(81, 82). Thus, injured proximal tubule cells modulate the amount and phenotype of infiltrating macrophages/DCs through production of cytokines.…”

MMP‐9‐positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice

“…15,16 MMP9 activity was inhibited using MMP9 inhibitor or MMP9-neutralizing antibody, which was administered daily for four consecutive days from day 0 to 3 (for early stage of UUO), 6 to 9 (for mid stage) or 10 to 13 (for late stage). 1,10,[21][22][23][24] Therefore, we hypothesized that neutrophil infiltration enhances renal fibrosis by promoting the expansion of inflammation and macrophage accumulation in the obstructed kidney; moreover, neutrophil produces MMP9 in the kidney to promote macrophage infiltration. Many reports demonstrated that inflammatory cells, including neutrophils, produce MMP9 during tissue injury.…”

“…10,[17][18][19][20] Previous results by us and other researchers also demonstrated that the early stage of UUO is the progression of inflammatory cell infiltration, and a high peak occurred from days 3-7. 1,10,[21][22][23][24] Therefore, we hypothesized that neutrophil infiltration enhances renal fibrosis by promoting the expansion of inflammation and macrophage accumulation in the obstructed kidney; moreover, neutrophil produces MMP9 in the kidney to promote macrophage infiltration.…”

Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3CL1/CX3CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis

“…Ly6‐C high inflammatory monocytes respond to inflammatory signals and leave the circulation by extravasation, whereas Ly6‐C low monocytes patrol the luminal side of the vasculature. Recent studies have demonstrated that Ly6‐C high inflammatory monocytes are increased in the tissues in mouse models of fibrosis, including lung fibrosis, unilateral ureteral obstruction–induced fibrosis, and bleomycin‐induced skin fibrosis . Depending on the specific cytokines to which they are exposed, tissue Ly6‐C high macrophages down‐regulate Ly‐6C and polarize cells into tissue‐remodeling/profibrotic (M2‐like) macrophages .…”