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

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 4S). Skin thickening and collagen deposition were significantly reduced in ovalbumin-sensitized skin of LTC 4S-deficient and type 2 cys-LT receptor (CysLT 2R)-deficient mice but not type 1 cys-LT receptor (CysLT 1R)-deficient mice. Adoptive transfer of bone marrow-derived eosinophils from WT but not LTC 4S-deficient mice restored skin thickening and collagen deposition in epicutaneous-sensitized skin of ΔdblGATA recipients. LTC 4stimulation caused increased collagen synthesis by human skin fibroblasts, which was blocked by CysLT 2R antagonism but not CysLT 1R 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 2R in the hyperkeratosis and fibrosis of allergic skin inflammation. Strategies that block eosinophil infiltration, cys-LT production, or the CysLT 2R might be useful in the treatment of AD.