Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer

Abstract

Phospholipase A 2 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 A 2 (sPLA 2 -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 3 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 sPLA 2 -IID as an immunosuppressive sPLA 2 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.

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

“…These differences can be explained, at least in part, by distinct localizations of these two sPLA 2 s in skin niches (see above) as well as by their distinct substrate specificities (see below), which could have different impacts on epidermal homeostasis and diseases. This view also contrasts with the exacerbation of psoriasis and contact dermatitis with augmented Th1/Th17 immune responses in mice lacking sPLA 2 -IID, a "resolving sPLA 2 " that is expressed in dendritic cells and regulates the functions of immune cells rather than keratinocytes by producing 3 PUFA-derived pro-resolving lipid mediators (37,48).…”

exSSSRs (extracellular S100 soil sensor receptors)‐Fc fusion proteins work as prominent decoys to S100A8/A9‐induced lung tropic cancer metastasis

“…Mmp13 also contributes to the maturation of immune‐suppressing Treg cells . Regarding to this, Il33 involves in activation of Treg cells and Pla2g2d plays a critical role in immune suppression . Hence, an immune suppressive environment triggered by them is possibly involved in onset of metastatic soil formation and after its ripeness.…”

Group IID, IIE, IIF and III secreted phospholipase A2s

“…Moreover, DCs isolated from Pla2g2d −/− mice are hyper-activated even in the absence of stimulation, with increased secretion of IFN-γ and elevated surface expression of MHC class II [25]. In contrast, acute skin inflammation as evaluated by irritant dermatitis is not affected by sPLA 2 -IID deficiency [31]. These results suggest that the lack of sPLA 2 -IID augments DCmediated Th1 immunity, rather than influencing T reg cell function and neutrophil-mediated acute inflammation.…”

“…In this state, expression levels of the signature Th1 cytokines IFN-γ and IL-12 are highly elevated in the draining LNs, whereas those of the T reg markers FOXP3 and IL-10 are unaffected, by sPLA 2 -IID deficiency. Even in the late stage of the sensitization phase, IFN-γ expression in the LNs is substantially elevated in Pla2g2d −/− mice [31]. Moreover, DCs isolated from Pla2g2d −/− mice are hyper-activated even in the absence of stimulation, with increased secretion of IFN-γ and elevated surface expression of MHC class II [25].…”

“…Although the properties and functions of sPLA 2 -IB, -IIA, -V and -X (see other reviews in this special issue) have been described in Table 1 Biological functions of sPLA 2 -IID, -IIE, -IIF and -III as revealed by studies using knockout (KO) and transgenic (TG) mice. Reduction of CHS and psoriasis [25,31] Increased anti-tumor immunity, Protection from skin cancer Decreased anti-tumor immunity [31] Production of PGD 2 Increased anti-viral immunity, Protection from SARS-induced pneumonia N.D. [46] PLA2G2E sPLA 2 -IIE Adipocytes Hydrolysis of minor lipoprotein phospholipids (e.g.…”