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Publication : Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis.

First Author  Saigusa R Year  2015
Journal  Proc Natl Acad Sci U S A Volume  112
Issue  49 Pages  15136-41
PubMed ID  26598674 Mgi Jnum  J:228133
Mgi Id  MGI:5705421 Doi  10.1073/pnas.1520997112
Citation  Saigusa R, et al. (2015) Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis. Proc Natl Acad Sci U S A 112(49):15136-41
abstractText  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.
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