Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3CL1/CX3CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Issue 11 (11th September 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Arthritis & rheumatology. Volume 71:Issue 11(2019)
• Page Start: 1923
• Page End: 1934
• Publication Date: 2019-09-11
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.41009
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: To assess the preclinical efficacy and mechanism of action of an anti‐CX3 CL1 monoclonal antibody (mAb) in systemic sclerosis (SSc). Methods: Cultured human dermal fibroblasts were used to evaluate the direct effect of anti‐CX3 CL1 mAb on fibroblasts. In addition, bleomycin‐induced and growth factor–induced models of SSc were used to investigate the effect of anti‐CX3 CL1 mAb on leukocyte infiltration, collagen deposition, and vascular damage in the skin. Results: Anti‐CX3 CL1 mAb 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 (TGFβ1). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX3 CL1 levels ( P < 0.05) and augmented lesional CX3 CL1 expression. Simultaneous administration of anti‐CX3 CL1 mAb or CX3 CR1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin ( P < 0.05). Injection of bleomycin induced expression of pSmad3 and TGFβ1 in the skin, which was inhibited by anti‐CX3 CL1 mAb. Further, the dermal infiltration of CX3 CR1+ cells, macrophages (inflammatory and alternatively activated [M2‐like] subsets), and CD3+ cells significantly decreased following anti‐CX3 CL1 mAb 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‐mCX3 CL1 mAb therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGFβ and connective tissue growth factor ( P < 0.01). Conclusion: Anti‐CX3 CL1 mAb therapy may be a novel approach for treating early skin fibrosis in inflammation‐driven fibrotic skin disorders such as SSc.