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Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15136-41. doi: 10.1073/pnas.1520997112. Epub 2015 Nov 23.

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

Author information

1
Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
2
Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan; yasano-tky@umin.ac.jp tada@m.u-tokyo.ac.jp.
3
Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan;
4
Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Meguro-ku, Tokyo 153-8505, Japan yasano-tky@umin.ac.jp tada@m.u-tokyo.ac.jp.

Abstract

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.

KEYWORDS:

Toll-like receptor 4; fibrosis; interferon regulatory factor 5; systemic sclerosis; vasculopathy

PMID:
26598674
PMCID:
PMC4679033
DOI:
10.1073/pnas.1520997112
[Indexed for MEDLINE]
Free PMC Article

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