文章基本信息

标题：Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis
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作者：Ryosuke Saigusa ; Yoshihide Asano ; Takashi Taniguchi 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：15136-15141
DOI：10.1073/pnas.1520997112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe present study is, to our knowledge, the first demonstration of the molecular mechanisms underlying the association of IFN regulatory factor 5 (IRF5) expression with milder clinical manifestations of systemic sclerosis (SSc). It is speculated that endogenous ligands induce Toll-like receptor 4 signaling and promote IRF5 transcriptional regulation of its target gene promoters, which may be required for the development of SSc. Our present study supports this notion. Symptoms associated with SSc in humans were suppressed in mice deficient in the Irf5 gene. As such, this study offers previously unidentified insight into the complexity of SSc pathology, giving impetus to further clinical studies for the treatment of the disease. Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5-/-) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5-/- mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.
关键词：interferon regulatory factor 5 ; systemic sclerosis ; fibrosis ; vasculopathy ; Toll-like receptor 4