title: Superoxide dismutase 3 suppresses hyaluronic acid fragments mediated skin inflammation by inhibition of toll-like receptor 4 signaling pathway: superoxide dismutase 3 inhibits reactive oxygen species-induced trafficking of toll-like receptor 4 to lipid rafts.
abstract: OBJECTIVE
  Hyaluronic acid (HA) is a component of the extracellular matrix and has been extensively applied for cosmetic, therapeutic, and antiaging purposes. However, HA fragments (HAFs) cause adverse effects. Considering that UV-exposure produces HAF that accumulated on the skin, the role of HAF in skin inflammation and its precise mechanism needs to be clarified, and strategies for the prevention of skin inflammation are necessary.
  
  
  RESULTS
  We found that extracellular superoxide dismutase (SOD), SOD3, suppresses HAF-mediated skin inflammation, while HAF mediated skin inflammation, macrophages and dendritic cells (DCs) dominantly infiltrate, up-regulating inflammatory cytokines and chemokines receptors. However, keratinocytes indirectly responded to HAF. Instead, epidermis containing keratinocytes were stimulated by secreted molecules from HAF-treated macrophages or DC and produced inflammatory molecules including chemokines, which, in turn, led to skin inflammation. This orchestrated inflammatory response was inhibited by SOD3. In addition, SOD3 inhibited DC maturation by suppressing the expression of major histocompatibility complex II, CD80, and CD86. Interestingly, these responses did not occur in Toll-like receptor 4 (TLR4) deficient mice. Similar to lipopolysaccharide (LPS), HAF promoted TLR4 translocation into the lipid rafts to initiate signaling. This trafficking was mediated, at least in part, by NAPDH oxidase-dependent reactive oxygen species (ROS) generation. Subsequently, nuclear factor kappa B (NFκB) subunit, p65, was recruited the promoters of genes encoding inflammatory molecules. This inflammatory machinery was blocked by SOD3.
  
  
  CONCLUSIONS
  Thus, we propose that SOD3 might provide an effective strategy for the treatment of HAF-mediated skin inflammation.
authors.affiliation: Laboratory of Dermato-Immunology, Catholic Research Institute of Medical Science, Catholic University, Seoul, South Korea.
authors.forename: Myung-Ja
authors.initials: MJ
authors.lastname: Kwon
authors.forename: Jihye
authors.initials: J
authors.lastname: Han
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Kim
authors.forename: Yun Sang
authors.initials: YS
authors.lastname: Lee
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; C441642:SOD3 protein, human; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase