Abstract
Phospholipase A2 enzymes have long been implicated in the promotion of inflammation by mobilizing pro-inflammatory lipid mediators, yet recent evidence suggests that they also contribute to anti-inflammatory or pro-resolving programs. Group IID-secreted phospholipase A2 (sPLA2-IID) is abundantly expressed in dendritic cells in lymphoid tissues and resolves the Th1 immune response by controlling the steady-state levels of anti-inflammatory lipids such as docosahexaenoic acid and its metabolites. Here, we show that psoriasis and contact dermatitis were exacerbated in Pla2g2d-null mice, whereas they were ameliorated in Pla2g2d-overexpressing transgenic mice, relative to littermate wild-type mice. These phenotypes were associated with concomitant alterations in the tissue levels of ω3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of pro-inflammatory and Th1/Th17-type cytokines in dendritic cells or lymph node cells. In the context of cancer, however, Pla2g2d deficiency resulted in marked attenuation of skin carcinogenesis, likely because of the augmented anti-tumor immunity. Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti-inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer.
Highlights
Endogenous mechanisms that orchestrate the resolution of inflammation are essential for tissue homeostasis
We examined the effect of Pla2g2d ablation on acute inflammation in the sensitization phase of contact hypersensitivity (CHS), which is equivalent to irritant dermatitis, as a model system
Consistent with the view that Pla2g2d expression in dendritic cells (DCs) or macrophages is down-regulated after cell activation [12, 29], its steady-state expression in the lymph nodes (LNs) was very high and markedly decreased 5 days after DNFB application (Fig. 1A, bottom panel)
Summary
Aggravated LN Inflammation in the Late Stage of Irritant Dermatitis in Pla2g2dϪ/Ϫ Mice—In a model of CHS, application of the hapten antigen dinitrofluorobenzene (DNFB) to abdominal skin (sensitization) followed by a second application of the same antigen to ear skin (elicitation) elicits Th1-driven ear swelling [13]. DNFB-treated mice on day 0 were stimulated with dinitrobenzene sulfonic acid (DNBS; a water-soluble form of DNFB) for 24 h ex vivo, PGD2 production, which depends on cPLA2␣ [15,16,17], was significantly greater in Pla2g2dϪ/Ϫ cells than in Pla2g2dϩ/ϩ cells (Fig. 1I) These results suggest that the lack of sPLA2-IID exacerbates the late stage of LN inflammation in the process of irritant dermatitis with augmentation of the proinflammatory PGD2-CRTH2 axis and an immunological shift toward an increased Th1 immune response, which may be dependent on the steady-state reduction of 3 PUFA metabolites. As opposed to Pla2g2d deficiency, its TG overexpression shifts the immune balance toward suppression of the anti-tumor immunity
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