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

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-δ^12,14-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.