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Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX 3 CL 1/ CX 3 CR 1 Pathway in Experimental Mouse Models of Systemic Sclerosis
Author(s) -
Luong Vu H.,
Utsunomiya Akira,
Chino Takenao,
Doanh Le H.,
Matsushita Takashi,
Obara Takashi,
Kuboi Yoshikazu,
Ishii Naoto,
Machinaga Akihito,
Ogasawara Hideaki,
Ikeda Wataru,
Kawano Tetsu,
Imai Toshio,
Oyama Noritaka,
Hasegawa Minoru
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41009
Subject(s) - bleomycin , chemistry , inflammation , fibrosis , fibronectin , infiltration (hvac) , microbiology and biotechnology , endocrinology , medicine , biology , extracellular matrix , biochemistry , materials science , chemotherapy , composite material
Objective To assess the preclinical efficacy and mechanism of action of an anti‐ CX 3 CL 1 monoclonal antibody ( mA b) in systemic sclerosis ( SS c). Methods Cultured human dermal fibroblasts were used to evaluate the direct effect of anti‐ CX 3 CL 1 mA b on fibroblasts. In addition, bleomycin‐induced and growth factor–induced models of SS c were used to investigate the effect of anti‐ CX 3 CL 1 mA b on leukocyte infiltration, collagen deposition, and vascular damage in the skin. Results Anti‐ CX 3 CL 1 mA b treatment significantly inhibited Smad3 phosphorylation ( P < 0.05) and expression of type I collagen and fibronectin 1 ( P < 0.01) in dermal fibroblasts stimulated with transforming growth factor β1 ( TGF β1). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX 3 CL 1 levels ( P < 0.05) and augmented lesional CX 3 CL 1 expression. Simultaneous administration of anti‐ CX 3 CL 1 mA b or CX 3 CR 1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin ( P < 0.05). Injection of bleomycin induced expression of pS mad3 and TGF β1 in the skin, which was inhibited by anti‐ CX 3 CL 1 mA b. Further, the dermal infiltration of CX 3 CR 1+ cells, macrophages (inflammatory and alternatively activated [M2‐like] subsets), and CD 3+ cells significantly decreased following anti‐ CX 3 CL 1 mA b therapy ( P < 0.05), as did the enhanced skin expression of fibrogenic molecules, such as thymic stromal lymphopoietin and secreted phosphoprotein 1 ( P < 0.05). However, the treatment did not significantly reduce established skin fibrosis. In the second model, simultaneous anti‐ mCX 3 CL 1 mA b therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGF β and connective tissue growth factor ( P < 0.01). Conclusion Anti‐ CX 3 CL 1 mA b therapy may be a novel approach for treating early skin fibrosis in inflammation‐driven fibrotic skin disorders such as SS c.