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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Oyoshi, MK; He, R; Kanaoka, Y; ElKhal, A; Kawamoto, S; Lewis, CN; Austen, KF; Geha, RS

Published Date

  • March 27, 2012

Published In

Volume / Issue

  • 109 / 13

Start / End Page

  • 4992 - 4997

Published By

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1203127109

Language

  • en