Pathogenic role of CCL2/MCP-1 in scleroderma

Abstract

Scleroderma is a connective tissue disease with unknown etiology characterized by excessive deposition of extracellular matrix in the skin. Cellular infiltrates of certain immune cells and proinflammatory mediators are suggested to play a crucial role in cutaneous fibrosis, forming complicated networks between fibroblasts and immune cells via cell-cell communications. Tissue-selective trafficking of leukocytes is mediated by combinations of adhesion molecules and chemokines. Recent studies have shown that an increase in proinflammatory chemokines has been associated with the initiation and/or development of fibrotic condition, suggesting that chemokines and their receptors may be important mediators of inflammation and fibrosis in scleroderma. In particular, CCL2/monocyte chemoattractant protein-1 (MCP-1) has been suggested to play an important role in scleroderma. This review will focus on the roles of CCL2 and its receptor during the process of cutaneous sclerosis, and also provide a current insight into the potential mechanisms of scleroderma.

The Role of Chemokines in Fibrotic Wound Healing

“…Many studies have emphasized the pathogenic role of MCP-1 (CCL2)/CCR2 axis in the induction of fibrosis, scleroderma, liver cirrhosis, atherosclerosis, pulmonary fibrosis, renal fibrosis, and colon fibrosis in human and animal models. [61][62][63][64][65] Utilizing a murine dermal fibrosis model induced by a subcutaneous injection of bleomycin into the dorsal skin of MCP-1 knockout mice, diminished induction of skin fibrosis was found in mice, suggesting that MCP-1 as a key determinant in the development of skin fibrosis was induced by bleomycin in vivo. 66 Mechanical force significantly modulates both T-celldependent inflammation and scar formation in another murine HTS model, in which as Th2 chemokine, MCP-1 signaling was involved.…”

Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling

“…1d,e). Notably, concentrations of MCP-1, a chemokine highly associated with inflammatory cell recruitment and fibrotic skin diseases 3–5,20–22 , were also less in FAK knockout wounds than in wild-type wounds (densitometry: 0.4 ± 0.05 for FAK knockout compared to 0.6 ± 0.07 for wild type (means ± s.e.m. ), P < 0.05) (Fig.…”

Updates on the pathophysiology of dermal sclerosis

“…In early-stage SSc, CCR2-positive fibroblasts show overexpression of α-SMA, CTGF and CCL2 [43], suggesting a potential autocrine regulation via the CCL2/CCR2 loop in SSc. The CCL2/CCR2 pathway contributes to the pathogenesis of dermal sclerosis [43], and inhibition of this signaling pathway by antagonists against CCR2 is currently under strategy for SSc in clinical trials [44].…”