title: Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis.
abstract: OBJECTIVE
  Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse are well-established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases, including SSc. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models.
  
  
  METHODS
  We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-) ;TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry.
  
  
  RESULTS
  Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis.
  
  
  CONCLUSIONS
  These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc.
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ichimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Noda
authors.forename: Kaname
authors.initials: K
authors.lastname: Akamata
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tada
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kadono
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D001761:Bleomycin