Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice.
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 ( approximately 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.
Matsushita
Yukiyo
Y
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Hasegawa
Minoru
M
Matsushita
Takashi
T
Fujimoto
Manabu
M
Horikawa
Mayuka
M
Fujita
Tomoyuki
T
Kawasuji
Ayako
A
Ogawa
Fumihide
F
Steeber
Douglas A
DA
Tedder
Thomas F
TF
Takehara
Kazuhiko
K
Sato
Shinichi
S
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology
D017252:CD3 Complex; D016207:Cytokines; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D003094:Collagen