Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 137, Issue 9, Pages 1850-1859Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2017.04.035
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Funding
- Ministry of Health, Labor, and Welfare of Japan
- Grants-in-Aid for Scientific Research [16H05366] Funding Source: KAKEN
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Dermal fibroblasts promote skin-localized transdifferentiation of regulatory T cells to T helper (Th) type 2-like cells in systemic sclerosis (SSc). However, the entire effect of SSc dermal fibroblasts on immune cells still remains unknown. Because galectin-9 induces Th2 cytokine-predominant immune imbalance by negatively regulating Th1/Th17 cells in inflammatory diseases, we investigated the contribution of galectin-9 to Th immune balance in SSc lesional skin. We used human clinical samples and Fli1(+/-) mice because Fli1 deficiency induces SSc-like phenotypes in various cell types. Galectin-9 was overexpressed in SSc dermal fibroblasts in vivo and in vitro. Serum galectin-9 levels were significantly elevated in SSc patients and positively correlated with skin score. Galectin-9 was up-regulated by autocrine endothelin stimulation and Fli1 deficiency, and Fli1 occupied the LGALS9 promoter in dermal fibroblasts. Co-culture of splenic CD4(+) T cells with Fli1(+/-) dermal fibroblasts significantly increased IL-4eproducing cell proportion, and this effect was cancelled in parallel with the increased interferon-g production when Fli1(+/-) dermal fibroblasts were transfected with Lgals9 small interfering RNA. Furthermore, Lgals9 small interfering RNA suppressed dermal collagen deposition by increasing interferon-g production of skin-infiltrating CD4(+) T cells in bleomycin-treated mice. These results suggest that SSc dermal fibroblasts suppress interferon-g expression of skin-infiltrating CD4(+) T cells through galectin-9 overproduction, promoting skin fibrosis development.
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