A critical role for C5L2 in the pathogenesis of experimental allergic asthma

Zhang Xun, Inken Schmudde, Yves Laumonnier, Mano J.K. Pandey, Jennifer R. Clark, Peter König, Norma P. Gerard, Craig Gerard, Marsha Wills-Karp, Jörg Köhl

Research output: Contribution to journalArticle

Abstract

The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The functional role of C5L2 in vivo remains enigmatic. In this study, we show in two models of OVA-and house dust mite (HDM)-induced experimental allergic asthma that C5L2-deficient mice are protected from the development of airway hyperresponsiveness, Th2 cytokine production, eosinophilic airway inflammation, serum IgE, or mucus production. Surprisingly, HDM-induced experimental asthma in C5L2-deficient mice was associated with increased pulmonary IL-17A production and increased airway neutrophil numbers. To directly assess the role of C5L2 on myeloid dendritic cells (mDCs) during allergen sensitization, we performed single or repeated adoptive transfers of C5L2-deficient mDCs into wild-type mice. HDM-pulsed C5L2-deficient mDCs induced strong Th2 cytokine production, which was associated with marked IFN-γ and IL-17A production, decreased eosinophil numbers, and reduced IgE production as compared with HDM-pulsed mDCs from wild-type mice. HDM stimulation of C5L2-/- mDCs in vitro resulted in production of Th17-promoting cytokine IL-23, which was absent in wild-type mDCs. Our findings suggest that C5L2 acts at the mDC/T cell interface to control the development of Th1 and Th17 cells in response to airway HDM exposure. Furthermore, it drives Th2 immune responses independent of mDCs, suggesting a complex role for C5L2 in the development of experimental allergic asthma.

Original languageEnglish (US)
Pages (from-to)6741-6752
Number of pages12
JournalJournal of Immunology
Volume185
Issue number11
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Xun, Z., Schmudde, I., Laumonnier, Y., Pandey, M. J. K., Clark, J. R., König, P., Gerard, N. P., Gerard, C., Wills-Karp, M., & Köhl, J. (2010). A critical role for C5L2 in the pathogenesis of experimental allergic asthma. Journal of Immunology, 185(11), 6741-6752. https://doi.org/10.4049/jimmunol.1000892