MKP-1 Deficiency Exacerbates Skin Fibrosis in a Mouse Model of Scleroderma

Abstract

Scleroderma is a chronic fibrotic disease, where proinflammatory and profibrotic events precede collagen accumulation. MKP-1 [mitogen-activated protein kinase (MAPK) phosphatase-1] downregulates inflammatory MAPK pathways suppressing inflammation. MKP-1 also supports Th1 polarization, which could shift Th1/Th2 balance away from profibrotic Th2 profile prevalent in scleroderma. In the present study, we investigated the potential protective role of MKP-1 in scleroderma. We utilized bleomycin-induced dermal fibrosis model as a well-characterized experimental model of scleroderma. Dermal fibrosis and collagen deposition as well as the expression of inflammatory and profibrotic mediators were analyzed in the skin samples. Bleomycin-induced dermal thickness and lipodystrophy were increased in MKP-1-deficient mice. MKP-1 deficiency enhanced collagen accumulation and increased expression of collagens, 1A1 and 3A1, in the dermis. Bleomycin-treated skin from MKP-1-deficient mice also showed enhanced expression of inflammatory and profibrotic factors IL-6, TGF-β1, fibronectin-1 and YKL-40, and chemokines MCP-1, MIP-1α and MIP-2, as compared to wild-type mice. The results show, for the first time, that MKP-1 protects from bleomycin-induced dermal fibrosis, suggesting that MKP-1 favorably modifies inflammation and fibrotic processes that drive the pathogenesis of scleroderma. Compounds enhancing the expression or activity of MKP-1 could thus prevent fibrotic processes in scleroderma and possess potential as a novel immunomodulative drug.

Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions

“…Fibroblasts can sense this protein and use it as a growth factor improving cell proliferation, survival, cell-matrix interactions and deposition of ECM during wound healing [ 54 – 56 ]. Recently, Scotece et al demonstrated that YKL-40 exhibited a sharp increase in skin in response to bleomycin treatment [ 57 ], and it has also been previously related to the progression of several inflammatory and fibrotic skin diseases, including systemic sclerosis, dermatitis and pyoderma gangrenosum [ 58 – 60 ]. Additionally, Ho et al (2014) demonstrated that a reduced population of primary dermal cells in culture (5–10% of total population) expresses YKL-40, but the expression was more widespread when the cells were treated with oncostatin M, a cytokine related to IL-6 family [ 61 ].…”