Tags

Type your tag names separated by a space and hit enter

Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis.

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.

Authors+Show Affiliations

University of Fukui, Fukui, Japan, and Hanoi Medical University, Hanoi, Vietnam.University of Fukui, Fukui, Japan.University of Fukui, Fukui, Japan.Hanoi Medical University, Hanoi, Vietnam.Kanazawa University, Kanazawa, Japan.Eisai Company, Ltd., Tsukuba, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.KAN Research Institute, Inc., Kobe, Japan.University of Fukui, Fukui, Japan.University of Fukui, Fukui, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31173491

Citation

Luong, Vu H., et al. "Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury By Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis." Arthritis & Rheumatology (Hoboken, N.J.), 2019.
Luong VH, Utsunomiya A, Chino T, et al. Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.). 2019.
Luong, V. H., Utsunomiya, A., Chino, T., Doanh, L. H., Matsushita, T., Obara, T., ... Hasegawa, M. (2019). Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Arthritis & Rheumatology (Hoboken, N.J.), doi:10.1002/art.41009.
Luong VH, et al. Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury By Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.). 2019 Jun 7; PubMed PMID: 31173491.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis. AU - Luong,Vu H, AU - Utsunomiya,Akira, AU - Chino,Takenao, AU - Doanh,Le H, AU - Matsushita,Takashi, AU - Obara,Takashi, AU - Kuboi,Yoshikazu, AU - Ishii,Naoto, AU - Machinaga,Akihito, AU - Ogasawara,Hideaki, AU - Ikeda,Wataru, AU - Kawano,Tetsu, AU - Imai,Toshio, AU - Oyama,Noritaka, AU - Hasegawa,Minoru, Y1 - 2019/06/07/ PY - 2019/01/24/received PY - 2019/06/04/accepted PY - 2019/6/8/pubmed PY - 2019/6/8/medline PY - 2019/6/8/entrez JF - Arthritis & rheumatology (Hoboken, N.J.) N2 - 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. SN - 2326-5205 UR - https://www.unboundmedicine.com/medline/citation/31173491/Blockade_of_the_CX3CL1-CX3CR1_Pathway_Inhibits_the_Progress_of_Skin_Inflammation,_Fibrosis,_and_Vascular_Injury_in_an_Experimental_Mouse_Model_of_Systemic_Sclerosis L2 - https://doi.org/10.1002/art.41009 DB - PRIME DP - Unbound Medicine ER -