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Intercellular Adhesion Molecule-1 Deficiency Attenuates the Development of Skin Fibrosis in Tight-Skin Mice¹

Yukiyo Matsushita^*, Minoru Hasegawa^2,*, Takashi Matsushita^*, Manabu Fujimoto^*, Mayuka Horikawa^*, Tomoyuki Fujita^*, Ayako Kawasuji^*, Fumihide Ogawa, Douglas A. Steeber, Thomas F. Tedder, Kazuhiko Takehara^* and Shinichi Sato

^* Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Dermatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan; Department of Biological Sciences, University of Wisconsin, Milwaukee, WI 53201; and Department of Immunology, Duke University Medical Center, Durham, NC 27710

The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis, develops cutaneous fibrosis. Although a fibrillin 1 gene mutation and immunological abnormalities have been demonstrated, the roles of adhesion molecules have not been investigated. To directly assess roles of adhesion molecules in skin fibrosis, TSK/+ mice lacking L-selectin and/or ICAM-1 were generated. The deficiency of ICAM-1, but not L-selectin, significantly suppressed (48%) the development of skin sclerosis in TSK/+ mice. Similarly, ICAM-1 antisense oligonucleotides inhibited skin fibrosis in TSK/+ mice. Although T cell infiltration was modest into the skin of TSK/+ mice, ICAM-1 deficiency down-regulated this migration, which is consistent with the established roles of endothelial ICAM-1 in leukocyte infiltration. In addition, altered phenotype or function of skin fibroblasts was remarkable and dependent on ICAM-1 expression in TSK/+ mice. ICAM-1 expression was augmented on TSK/+ dermal fibroblasts stimulated with IL-4. Although growth or collagen synthesis of TSK/+ fibroblasts cultured with IL-4 was up-regulated, it was suppressed by the loss or blocking of ICAM-1. Collagen expression was dependent on the strain of fibroblasts, but not on the strain of cocultured T cells. Thus, our findings indicate that ICAM-1 expression contributes to the development of skin fibrosis in TSK/+ mice, especially via ICAM-1 expressed on skin fibroblasts.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant-in-aid from the Ministry of Health and Welfare of Japan (to M.H. and S.S.), Kanazawa University (to M.H.), Nagasaki University (to S.S.), a project research for Japan Rheumatism Foundation (to S.S.), the Arthritis Foundation (to T.F.T.), and National Institutes of Health (CA105001, CA96547, and AI56363 to T.F.T.).

² Address correspondence and reprint requests to Dr. Minoru Hasegawa, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan. E-mail address: minoruha{at}derma.m.kanazawa-u.ac.jp

³ Abbreviations used in this paper: SSc, systemic sclerosis; ANA, antinuclear Ab; Ct, threshold cycle; ECM, extracellular matrix; TSK, tight skin.