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Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis.

Abstract

OBJECTIVE

To assess the preclinical efficacy and mechanism of action of an anti-CX3CL1 monoclonal antibody (mAb) in systemic sclerosis (SSc).

METHODS

Cultured human dermal fibroblasts were used to evaluate the direct effect of anti-CX3CL1mAb on fibroblasts. In addition, bleomycin and growth factor-induced SSc models were used to investigate the effect of anti-CX3CL1mAb on leukocyte infiltration, collagen deposition, and vascular damage in the skin.

RESULTS

Anti-CX3CL1mAb treatment significantly inhibited Smad3 phosphorylation (p<0.05) and expression of collagen I and fibronectin 1 (p<0.01) in dermal fibroblasts stimulated with TGF-β1. In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX3CL1 levels (p<0.05) and augmented lesional CX3CL1 expression. Simultaneous administration of anti-CX3CL1mAb or CX3CR1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin (p<0.05). Injection of bleomycin induced expression of phosphorylated Smad3 and TGF-β1 in the skin, which was inhibited by anti-CX3CL1mAb. Further, the dermal infiltration of CX3CR1+ cells, macrophages (inflammatory and M2-like subsets), and CD3+ cells significantly decreased following anti-CX3CL1mAb 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 the established skin fibrosis. In the second model, simultaneous anti-mCX3CL1mAb therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of transforming growth factor-β and connective tissue growth factor (p<0.01).

CONCLUSION

Anti-CX3CL1mAb therapy may be a novel approach for early skin fibrosis in inflammation-driven fibrotic skin disorders such as SSc. This article is protected by copyright. All rights reserved.

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  • Authors+Show Affiliations

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    Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan. Department of Dermatology, Hanoi Medical University, Hanoi.

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    Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

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    Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

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    Department of Dermatology, Hanoi Medical University, Hanoi.

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    Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-8641, Japan.

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    Eisai Co., Ltd. Tsukuba, 300-2635, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    KAN Research Institute, Inc, Kobe, Hyogo, 650-0047, Japan.

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    Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

    Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31173491

    Citation

    Luong, Vu H., et al. "Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis." Arthritis & Rheumatology (Hoboken, N.J.), 2019.
    Luong VH, Utsunomiya A, Chino T, et al. Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.). 2019.
    Luong, V. H., Utsunomiya, A., Chino, T., Le, D. H., Matsushita, T., Obara, T., ... Hasegawa, M. (2019). Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis. Arthritis & Rheumatology (Hoboken, N.J.), doi:10.1002/art.41009.
    Luong VH, et al. Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model 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 - Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis. AU - Luong,Vu H, AU - Utsunomiya,Akira, AU - Chino,Takenao, AU - Le,Doanh 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 - 2019/6/8/entrez JF - Arthritis & rheumatology (Hoboken, N.J.) N2 - OBJECTIVE: To assess the preclinical efficacy and mechanism of action of an anti-CX3CL1 monoclonal antibody (mAb) in systemic sclerosis (SSc). METHODS: Cultured human dermal fibroblasts were used to evaluate the direct effect of anti-CX3CL1mAb on fibroblasts. In addition, bleomycin and growth factor-induced SSc models were used to investigate the effect of anti-CX3CL1mAb on leukocyte infiltration, collagen deposition, and vascular damage in the skin. RESULTS: Anti-CX3CL1mAb treatment significantly inhibited Smad3 phosphorylation (p<0.05) and expression of collagen I and fibronectin 1 (p<0.01) in dermal fibroblasts stimulated with TGF-β1. In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX3CL1 levels (p<0.05) and augmented lesional CX3CL1 expression. Simultaneous administration of anti-CX3CL1mAb or CX3CR1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin (p<0.05). Injection of bleomycin induced expression of phosphorylated Smad3 and TGF-β1 in the skin, which was inhibited by anti-CX3CL1mAb. Further, the dermal infiltration of CX3CR1+ cells, macrophages (inflammatory and M2-like subsets), and CD3+ cells significantly decreased following anti-CX3CL1mAb 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 the established skin fibrosis. In the second model, simultaneous anti-mCX3CL1mAb therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of transforming growth factor-β and connective tissue growth factor (p<0.01). CONCLUSION: Anti-CX3CL1mAb therapy may be a novel approach for early skin fibrosis in inflammation-driven fibrotic skin disorders such as SSc. This article is protected by copyright. All rights reserved. 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 -