Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model

Ayumi Yoshizaki, Koichi Yanaba, Yohei Iwata, Kazuhiro Komura, Asako Ogawa, Yuichiro Akiyama, Eiji Muroi, Toshihide Hara, Fumihide Ogawa, Motoi Takenaka, Kazuhiro Shimizu, Minoru Hasegawa, Manabu Fujimoto, Thomas F. Tedder, Shinichi Sato

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Mice s.c. injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules and does not require Ag sensitization. To assess the role of adhesion molecules in this pathogenetic process, bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. In contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or P-selectin glycoprotein ligand 1 (PSGL-1) deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, whereas Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis.

Original languageEnglish
Pages (from-to)2502-2515
Number of pages14
JournalJournal of Immunology
Volume185
Issue number4
DOIs
Publication statusPublished - 15-08-2010

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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