Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators

Yoshimi Miki, Kei Yamamoto, Yoshitaka Taketomi, Hiroyasu Sato, Kanako Shimo, Tetsuyuki Kobayashi, Yukio Ishikawa, Toshiharu Ishii, Hiroki Nakanishi, Kazutaka Ikeda, Ryo Taguchi, Kenji Kabashima, Makoto Arita, Hiroyuki Arai, Gérard Lambeau, James M. Bollinger, Shuntaro Hara, Michael H. Gelb, Makoto Murakami

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Resolution of inflammation is an active process that is mediated in part by antiinflammatory lipid mediators. Although phospholipase A2 (PLA2) enzymes have been implicated in the promotion of inflammation through mobilizing lipid mediators, the molecular entity of PLA2 subtypes acting upstream of antiinflammatory lipid mediators remains unknown. Herein, we show that secreted PLA2 group IID (PLA2G2D) is preferentially expressed in CD11c+ dendritic cells (DCs) and macrophages and displays a pro-resolving function. In hapten-induced contact dermatitis, resolution, not propagation, of inflammation was compromised in skin and LNs of PLA2G2D-deficient mice (PLA2g2d-/-), in which the immune balance was shifted toward a proinflammatory state over an antiinflammatory state. Bone marrow-derived DCs from PLA2g2d-/- mice were hyperactivated and elicited skin inflammation after intravenous transfer into mice. Lipidomics analysis revealed that PLA2G2D in the LNs contributed to mobilization of a pool of polyunsaturated fatty acids that could serve as precursors for antiinflammatory/pro-resolving lipid mediators such as resolvin D1 and 15-deoxy-δ12,14-prostaglandin J, which reduced Th1 cytokine production and surface MHC class II expression in LN cells or DCs. Altogether, our results highlight PLA2G2D as a "resolving sPLA2" that ameliorates inflammation through mobilizing pro-resolving lipid mediators and points to a potential use of this enzyme for treatment of inflammatory disorders.

Original languageEnglish
Pages (from-to)1217-1234
Number of pages18
JournalJournal of Experimental Medicine
Volume210
Issue number6
DOIs
Publication statusPublished - 2013 Jun
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Miki, Y., Yamamoto, K., Taketomi, Y., Sato, H., Shimo, K., Kobayashi, T., Ishikawa, Y., Ishii, T., Nakanishi, H., Ikeda, K., Taguchi, R., Kabashima, K., Arita, M., Arai, H., Lambeau, G., Bollinger, J. M., Hara, S., Gelb, M. H., & Murakami, M. (2013). Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. Journal of Experimental Medicine, 210(6), 1217-1234. https://doi.org/10.1084/jem.20121887