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Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of

Authors: Michiko K Oyoshi|||Rui He|||Yoshihide Kanaoka|||Abdallah ElKhal|||Seiji Kawamoto|||Christopher N Lewis|||K Frank Austen|||Raif S Geha

Journal: Proceedings of the National Academy of Sciences of the United States of America

Publication Type: Journal Article

Date: 2012

DOI: PMC3323994

ID: 22416124

Affiliations:

Affiliations

    Division of Immunology, Children's Hospital, Boston, MA 02115, USA.|||||||||||||||||||||

Abstract

Atopic dermatitis (AD) skin lesions exhibit epidermal and dermal thickening, eosinophil infiltration, and increased levels of the cysteinyl leukotriene (cys-LT) leukotriene C(4) (LTC(4)). Epicutaneous sensitization with ovalbumin of WT mice but not ΔdblGATA mice, the latter of which lack eosinophils, caused skin thickening, collagen deposition, and increased mRNA expression of the cys-LT generating enzyme LTC(4) synthase (LTC(4)S). Skin thickening and collagen deposition were significantly reduced in ovalbumin-sensitized skin of LTC(4)S-deficient and type 2 cys-LT receptor (CysLT(2)R)-deficient mice but not type 1 cys-LT receptor (CysLT(1)R)-deficient mice. Adoptive transfer of bone marrow-derived eosinophils from WT but not LTC(4)S-deficient mice restored skin thickening and collagen deposition in epicutaneous-sensitized skin of ΔdblGATA recipients. LTC(4) stimulation caused increased collagen synthesis by human skin fibroblasts, which was blocked by CysLT(2)R antagonism but not CysLT(1)R antagonism. Furthermore, LTC(4) stimulated skin fibroblasts to secrete factors that elicit keratinocyte proliferation. These findings establish a role for eosinophil-derived cys-LTs and the CysLT(2)R in the hyperkeratosis and fibrosis of allergic skin inflammation. Strategies that block eosinophil infiltration, cys-LT production, or the CysLT(2)R might be useful in the treatment of AD.


Chemical List

    GATA Transcription Factors|||Receptors, Leukotriene|||Leukotriene C4|||Ovalbumin|||Collagen|||cysteinyl leukotriene receptor 2|||Glutathione Transferase|||leukotriene-C4 synthase|||leukotriene D4 receptor

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