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Gene from a Psoriasis Susceptibility Locus Primes the Skin for Inflammation

  1. Author:
    Wolf, R.
    Mascia, F.
    Dharamsi, A.
    Howard, O. M. Z.
    Cataisson, C.
    Bliskovski, V.
    Winston, J.
    Feigenbaum, L.
    Lichti, U.
    Ruzicka, T.
    Chavakis, T.
    Yuspa, S. H.

  2. Author Address

    [Wolf, Ronald; Mascia, Francesca; Dharamsi, Alif; Cataisson, Christophe; Bliskovski, Val; Winston, Jason; Lichti, Ulrike; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Wolf, Ronald; Ruzicka, Thomas] Univ Munich, Dept Dermatol & Allergol, D-80337 Munich, Germany. [Howard, O. M. Zack] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Feigenbaum, Lionel] Sci Applicat Int Corp, Lab Anim Sci Program, Frederick, MD 21702 USA. [Chavakis, Triantafyllos] NCI, Expt Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Chavakis, Triantafyllos] Tech Univ Dresden, Dept Med, Div Vasc Inflammat Diabet & Kidney, D-01307 Dresden, Germany. [Chavakis, Triantafyllos] Tech Univ Dresden, Inst Physiol, D-01307 Dresden, Germany.;Yuspa, SH, NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA.;yuspas@mail.nih.gov
    1. Year: 2010
    2. Date: Dec
  2. Journal: Science Translational Medicine
    1. 2
    2. 61
    3. Pages: 10
  4. Type of Article: Article
  5. Article Number: 61ra90
  6. ISSN: 1946-6234
  1. Abstract:

    Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T(H)1) and T(H)17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.

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External Sources

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  2. DOI: 10.1126/scitranslmed.3001108
  3. View record in Web of Science®
  4. WOS: 000288443500002

Library Notes

  1. Fiscal Year: FY2010-2011
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