title: Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis.
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.
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Saigusa
authors.affiliation: 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.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshizaki
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan;
authors.forename: Koji
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuruta
authors.affiliation: 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.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan;
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012595:Scleroderma, Systemic / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Toll-like receptor 4; fibrosis; interferon regulatory factor 5; systemic sclerosis; vasculopathy