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

Publication ,  Journal Article
Oyoshi, MK; He, R; Kanaoka, Y; ElKhal, A; Kawamoto, S; Lewis, CN; Austen, KF; Geha, RS
Published in: Proceedings of the National Academy of Sciences of the United States of America
March 2012

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.

Duke Scholars

Published In

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

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

March 2012

Volume

109

Issue

13

Start / End Page

4992 / 4997

Related Subject Headings

  • Skin
  • Signal Transduction
  • Receptors, Leukotriene
  • Ovalbumin
  • Mice
  • Leukotriene C4
  • Keratinocytes
  • Immunization
  • Humans
  • Glutathione Transferase
 

Citation

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Oyoshi, M. K., He, R., Kanaoka, Y., ElKhal, A., Kawamoto, S., Lewis, C. N., … Geha, R. S. (2012). Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proceedings of the National Academy of Sciences of the United States of America, 109(13), 4992–4997. https://doi.org/10.1073/pnas.1203127109
Oyoshi, Michiko K., Rui He, Yoshihide Kanaoka, Abdallah ElKhal, Seiji Kawamoto, Christopher N. Lewis, K Frank Austen, and Raif S. Geha. “Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis.Proceedings of the National Academy of Sciences of the United States of America 109, no. 13 (March 2012): 4992–97. https://doi.org/10.1073/pnas.1203127109.
Oyoshi MK, He R, Kanaoka Y, ElKhal A, Kawamoto S, Lewis CN, et al. Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proceedings of the National Academy of Sciences of the United States of America. 2012 Mar;109(13):4992–7.
Oyoshi, Michiko K., et al. “Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis.Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 13, Mar. 2012, pp. 4992–97. Epmc, doi:10.1073/pnas.1203127109.
Oyoshi MK, He R, Kanaoka Y, ElKhal A, Kawamoto S, Lewis CN, Austen KF, Geha RS. Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proceedings of the National Academy of Sciences of the United States of America. 2012 Mar;109(13):4992–4997.
Journal cover image

Published In

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

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

March 2012

Volume

109

Issue

13

Start / End Page

4992 / 4997

Related Subject Headings

  • Skin
  • Signal Transduction
  • Receptors, Leukotriene
  • Ovalbumin
  • Mice
  • Leukotriene C4
  • Keratinocytes
  • Immunization
  • Humans
  • Glutathione Transferase