Roles of secreted phospholipase A2 group IIA in inflammation and host defense

Doré, Étienne; Boilard, Éric

doi:10.1016/j.bbalip.2018.08.017

Cited by 68 publications

(91 citation statements)

References 195 publications

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“…Thus, sPLA 2 -IIA is primarily involved in host defense by killing bacteria and triggering innate immunity, while over-amplification of the response leads to exacerbation of inflammation by hydrolyzing EVs ( Figure 1 ). These dual functions of sPLA 2 -IIA were summarized in a recent review [ 25 ].…”

Section: The Spla 2 Familymentioning

confidence: 99%

Updating Phospholipase A2 Biology

2020

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The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo.

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Section: The Spla 2 Familymentioning

confidence: 99%

Updating Phospholipase A2 Biology

2020

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“…Figure 5 displays a simplified summary of the arachidonic acid cascade that lists some of the most important downstream inflammatory mediator products, but there are over a hundred eicosanoids, including the metabolites of cytochrome P450 (CYP) enzymes, that are important signalling mediators for the normal cell function [ 35 ]. hGIIA may hydrolyze the mitochondrial membrane and release AA, lyso-cardiolipin and mitochondrial DNA, which in turn can be recognized as damage-associated molecular patterns (DAMPs) and participate in pro-inflammatory pathways [ 36 ]. Although the catalytic activity of PLA 2 s initiates the eicosanoid cascade by liberating AA, the final biological outcome from this is heavily dependent on the types of downstream enzymes in the system.…”

Section: Biological Role Of Hgiiamentioning

confidence: 99%

“…It is observed to potently and selectively cause lysis of the gram-positive bacteria without affecting the corneal epithelial cells, although it was ineffective against gram-negative bacteria in the absence of bacterial permeability inducing protein (BPIP) [ 59 ]. Reviews of hGIIA as it relates to host defense have recently been provided [ 36 , 60 ]. The role of hGIIA with respect to innate immunity and resistance mechanisms are potentially complex and do not necessarily relate only to the bacterial membrane composition, and the role of GIIA in the microbiome could be a very important contribution to beneficial bacterial colonization.…”

Section: Biological Role Of Hgiiamentioning

confidence: 99%

Structural and Functional Aspects of Targeting the Secreted Human Group IIA Phospholipase A2

et al. 2020

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Human group IIA secretory phospholipase A2 (hGIIA) promotes the proliferation of cancer cells, making it a compelling therapeutic target, but it is also significant in other inflammatory conditions. Consequently, suitable inhibitors of hGIIA have always been sought. The activation of phospholipases A2 and the catalysis of glycerophospholipid substrates generally leads to the release of fatty acids such as arachidonic acid (AA) and lysophospholipid, which are then converted to mediator compounds, including prostaglandins, leukotrienes, and the platelet-activating factor. However, this ability of hGIIA to provide AA is not a complete explanation of its biological role in inflammation, as it has now been shown that it also exerts proinflammatory effects by a catalysis-independent mechanism. This mechanism is likely to be highly dependent on key specific molecular interactions, and the full mechanistic descriptions of this remain elusive. The current candidates for the protein partners that may mediate this catalysis-independent mechanism are also introduced in this review. A key discovery has been that selective inhibition of the catalysis-independent activity of hGIIA is achieved with cyclised derivatives of a pentapeptide, FLSYK, derived from the primary sequence of hGIIA. The effects of hGIIA on cell function appear to vary depending on the pathology studied, and so its mechanism of action is complex and context-dependent. This review is comprehensive and covers the most recent developments in the understanding of the many facets of hGIIA function and inhibition and the insight they provide into their clinical application for disease treatment. A cyclic analogue of FLSYK, c2, the most potent analogue known, has now been taken into clinical trials targeting advanced prostate cancer.

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“…However, no approaches were undertaken to characterize the cellular responses to exogenously added sPLA 2 enzymes. It has been suggested that the response of cells exposed to exogenous sPLA 2 is dependent upon the nature of the lipid mediator generated on the membrane where the sPLA 2 acts [ 29 ]. However, it is also known that some sPLA 2 s lack catalytic activity but still exert potent biological actions [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

A Lipidomic Perspective of the Action of Group IIA Secreted Phospholipase A2 on Human Monocytes: Lipid Droplet Biogenesis and Activation of Cytosolic Phospholipase A2α

et al. 2020

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Phospholipase A2s constitute a wide group of lipid-modifying enzymes which display a variety of functions in innate immune responses. In this work, we utilized mass spectrometry-based lipidomic approaches to investigate the action of Asp-49 Ca2+-dependent secreted phospholipase A2 (sPLA2) (MT-III) and Lys-49 sPLA2 (MT-II), two group IIA phospholipase A2s isolated from the venom of the snake Bothrops asper, on human peripheral blood monocytes. MT-III is catalytically active, whereas MT-II lacks enzyme activity. A large decrease in the fatty acid content of membrane phospholipids was detected in MT III-treated monocytes. The significant diminution of the cellular content of phospholipid-bound arachidonic acid seemed to be mediated, in part, by the activation of the endogenous group IVA cytosolic phospholipase A2α. MT-III triggered the formation of triacylglycerol and cholesterol enriched in palmitic, stearic, and oleic acids, but not arachidonic acid, along with an increase in lipid droplet synthesis. Additionally, it was shown that the increased availability of arachidonic acid arising from phospholipid hydrolysis promoted abundant eicosanoid synthesis. The inactive form, MT-II, failed to produce any of the effects described above. These studies provide a complete lipidomic characterization of the monocyte response to snake venom group IIA phospholipase A2, and reveal significant connections among lipid droplet biogenesis, cell signaling and biochemical pathways that contribute to initiating the inflammatory response.

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Roles of secreted phospholipase A2 group IIA in inflammation and host defense

Cited by 68 publications

References 195 publications

Updating Phospholipase A2 Biology

Updating Phospholipase A2 Biology

Structural and Functional Aspects of Targeting the Secreted Human Group IIA Phospholipase A2

A Lipidomic Perspective of the Action of Group IIA Secreted Phospholipase A2 on Human Monocytes: Lipid Droplet Biogenesis and Activation of Cytosolic Phospholipase A2α

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