MKP-1 Deficiency Exacerbates Skin Fibrosis in a Mouse Model of Scleroderma
Scotece, Morena; Hämäläinen, Mari; Leppänen, Tiina; Vuolteenaho, Katriina; Moilanen, Eeva (2023)
Scotece, Morena
Hämäläinen, Mari
Leppänen, Tiina
Vuolteenaho, Katriina
Moilanen, Eeva
2023
4668
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202303293311
https://urn.fi/URN:NBN:fi:tuni-202303293311
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [17098]