Blockade of CCR2 Ameliorates Progressive Fibrosis in Kidney

Abstract

Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. Importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-␤, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys. Fibrosis is characteristic in progressive diseases, resulting in organ failure. Monocyte chemoattractant protein (MCP)-1 (also termed as monocyte chemotactic and activating factor/CCL2) is presumed to be a key molecule in chemotaxis and activation of macrophages.

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

“…1) because it has been previously reported that renal macrophages but not DCs mediate fibrosis in this model (16,18,66). However, Cx 3 cr1 GFP/GFP mice possessed similar or lower numbers of GFP + renal phagocytes under homeostatic conditions, in experimental glomerulonephritis and in kidney infection compared with CX 3 CR1-competent controls (3, 58), consistent with our present findings in UUO ( Fig.…”

“…In contrast, inappropriate macrophage functions promoted fibrosis in various organs (13,14). In the kidney, macrophages but not DCs mediated fibrosis in unilateral ureter ligation (UUO) and after ischemia/reperfusion (15)(16)(17)(18). Several mechanisms contribute to renal fibrosis, including the production of the main profibrotic molecule TGF-b (14,19).…”

“…Inflammatory Gr1 + macrophages possess profibrotic properties (42), and their depletion or genetic CCR2 deficiency attenuated tissue damage and fibrosis in UUO (16), lupus nephritis (43), and ischemia/ reperfusion (44). Also, CX 3 CR1 has been implicated in monocyte recruitment into inflamed tissues, like arteriosclerotic vessels (45), the listeria-infected spleen (46), the eye (47), in colitis models (28), or the skin (48).…”

Fibrocytes are involved in the pathogenesis of human chronic kidney disease

“…Especially, the severity of interstitial fibrosis has been reported to determine the prognosis of kidney function [2]. To date, resident fibroblasts, epithelial-mesenchymal transition (EMT)-derived fibroblasts/myofibroblasts, and monocytes/macrophages have been suggested to be involved in the progression of kidney diseases [3,4]. However, the precise pathogenic mechanisms of tubulointerstitial lesions, especially related to interstitial fibrosis, in patients with CKD remain to be determined.…”

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

“…Likewise, cross-linking of myeloid IgA Fc receptors (Fc␣RI or CD89) aggravates IgA nephropathy and anti-GBM nephritis in an FcR␥-dependent manner (10). Macrophages and T cells are important in the inflammation associated with ureteral obstruction, another common cause of ESRD (11)(12)(13)(14)(15)(16). Conventional antiinflammatory therapy for ESRD, based on steroids, immunosuppressants, and angiotensin-converting enzyme inhibitors have limited efficacy on disease progression (17).…”