Role of human group IIA secreted phospholipase A2 in malaria pathophysiology: Insights from a transgenic mouse model

Dacheux, Mélanie; Chaouch, Soraya; Alonso, Joy; Labat, Amandine; Payré, Christine; Petit-Paitel, Agnès; Bihl, Franck; Lagrange, Isabelle; Grellier, Philippe; Touqui, Lhousseine; Lambeau, Gérard; Deregnaucourt, Christiane

doi:10.1016/j.biochi.2021.06.009

Cited by 6 publications

(7 citation statements)

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“…Initial studies of PLA2G2A found that it is induced by several cytokines and second messengers, including interleukins 1 and 6 (IL-1, IL-6), tumor necrosis factor alpha, interferon-γ, lipopolysaccharides, and cyclic AMP (cAMP), suggesting a pro-inflammatory role. [20][21][22] PLA2G2A hydrolyzes oxLDL, 23 and elevated serum PLA2G2A levels have been labeled as a biomarker for cardiovascular diseases. 24 In patients with metabolic syndrome, high levels of plasma PLA2G2A are a predictor for early stage atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

et al. 2021

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Group IIA secreted phospholipase A2 (PLA2G2A) hydrolyzes glycerophospholipids at the sn-2 position resulting in the release of fatty acids and lysophospholipids. C57BL/6 mice do not express Pla2g2a due to a frameshift mutation (wild-type [WT] mice). We previously reported that transgenic expression of human PLA2G2A in C57BL/6 mice (IIA+ mice) protects against weight gain and insulin resistance, in part by increasing total energy expenditure. Additionally, we found that brown and white adipocytes from IIA+ mice have increased expression of mitochondrial uncoupling markers, such as uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator, and PR domain containing 16, suggesting that the energy expenditure phenotype might be due to an increased thermogenic capacity in adipose tissue. Here, we further characterize the impact of PLA2G2A on thermogenic mechanisms in adipose tissue. Metabolic analysis of WT and IIA+ mice revealed that even when housed within their thermoneutral zone, IIA+ mice have elevated energy expenditure compared to WT littermates. Increased energy expenditure in IIA+ mice is associated with increased citrate synthase activity in brown adipose tissue (BAT) and increased mitochondrial respiration in both brown and white adipocytes. We also observed that direct addition of recombinant PLA2G2A enzyme to in vitro cultured adipocytes results in the marked induction of UCP1 protein expression. Finally, we report that PLA2G2A induces the expression of numerous transcripts related to energy substrate transport and metabolism in BAT, suggestive of an increase in substrate flux to fuel BAT activity. These data demonstrate that PLA2G2A enhances adipose tissue thermogenesis, in part, through elevated substrate delivery and increased mitochondrial content in BAT.

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Section: Introductionmentioning

confidence: 99%

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

et al. 2021

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“…Prior to studies using KO mice for various sPLA 2 s, studies using sPLA 2 -overexpressing TG mice had provided several informative hints for the potential pathophysiological functions of sPLA 2 s . 16,19,24,44,52,78,[84][85][86][90][91][92][93][95][96][97][98][100][101][102][103]105 Here, we describe general aspects in brief, rather than detailing the individual phenotypes, of sPLA 2 -TG mice. It is notable that, as opposed to the classical theory that sPLA 2 s are generally involved in inflammation by producing pro-inflammatory eicosanoids, not all sPLA 2 -TG mice display pro-inflammatory phenotypes.…”

Section: In S I G Hts From S Pl a Tr Ansg Enic Micementioning

confidence: 99%

“…Exacerbation of atherosclerosis [95,96] Global TG Protection against malaria infection [97] Global TG Uncertain Increase in adipose tissue thermogenesis [98] sPLA Reduced adiposity [16] sPLA 2 -X PLA2G10 Global TG Increase in ω3 PUFAs and their metabolites Systemic anti-inflammation [24] Global TG Increase in P-LPE (mimicking Pla2g2f-Tg)?…”

Section: Increased Hydrolysis Of Lipoproteins To Release Oxidized Pufasmentioning

confidence: 99%

“…This anti-malaria effect is likely because sPLA 2 -IIA, and possibly other sPLA 2 s such as sPLA 2 -IIF and -X, can suppress malaria growth by releasing toxic oxidized PUFAs from lipoproteins (Figure 3C). 97,116 In PLA2G2A-TG mice, in which sPLA 2 -IIA expression is driven by the human PLA2G2A gene promoter, its mRNA expression is elevated in the liver but not in the spleen and blood cells, suggesting that the liver may be a main source of circulating sPLA 2 -IIA. However, it remains unclear whether the plasma concentration of sPLA 2 -IIA or other sPLA 2 s could reach the level enough to kill the parasite in malaria patients.…”

Section: Malaria Infectionmentioning

confidence: 99%

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Modulation of immunity by the secreted phospholipase A₂ family

Murakami

Sato

Taketomi

2023

Immunological Reviews

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SummaryAmong the phospholipase A2 (PLA2) superfamily, which typically catalyzes the sn‐2 hydrolysis of phospholipids to yield fatty acids and lysophospholipids, the secreted PLA2 (sPLA2) family contains 11 isoforms in mammals. Individual sPLA2s have unique enzymatic specificity toward fatty acids and polar heads of phospholipid substrates and display distinct tissue/cellular distributions, suggesting their distinct physiological functions. Recent studies using knockout and/or transgenic mice for a full set of sPLA2s have revealed their roles in modulation of immunity and related disorders. Application of mass spectrometric lipidomics to these mice has enabled to identify target substrates and products of individual sPLA2s in given tissue microenvironments. sPLA2s hydrolyze not only phospholipids in the plasma membrane of activated, damaged or dying mammalian cells, but also extracellular phospholipids such as those in extracellular vesicles, microbe membranes, lipoproteins, surfactants, and dietary phospholipids, thereby exacerbating or ameliorating various diseases. The actions of sPLA2s are dependent on, or independent of, the generation of fatty acid‐ or lysophospholipid‐derived lipid mediators according to the pathophysiological contexts. In this review, we make an overview of our current understanding of the roles of individual sPLA2s in various immune responses and associated diseases.

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“…The most studied member, sPLA 2 -IIA, has a demonstrated primary function in host defense against invading pathogens ( Doré and Boilard, 2019 ; Scott et al, 2021 ; Miki et al, 2022 ). As a secreted lipolytic enzyme, sPLA 2 -IIA shows bactericidal activity through hydrolysis of Gram-positive membranes ( Weinrauch et al, 1998 ), and anti-parasitic function through hydrolysis of oxidized phospholipids in the plasma lipoproteins of malaria patients, thus promoting P lasmodium falciparum killing effect ( Dacheux et al, 2019 ; Dacheux et al, 2021 ). Secreted PLA 2 -IIA is also referred as an inflammatory enzyme and amplifier of innate immune responses ( Doré and Boilard, 2019 ; Doré et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

Mangini

D’Angelo

Vinciguerra

et al. 2022

Front. Cell Dev. Biol.

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Increasing evidence points to the involvement of group IIA secreted phospholipase A2 (sPLA2-IIA) in pathologies characterized by abnormal osteoclast bone-resorption activity. Here, the role of this moonlighting protein has been deepened in the osteoclastogenesis process driven by the RANKL cytokine in RAW264.7 macrophages and bone-marrow derived precursor cells from BALB/cJ mice. Inhibitors with distinct selectivity toward sPLA2-IIA activities and recombinant sPLA2-IIA (wild-type or catalytically inactive forms, full-length or partial protein sequences) were instrumental to dissect out sPLA2-IIA function, in conjunction with reduction of sPLA2-IIA expression using small-interfering-RNAs and precursor cells from Pla2g2a knock-out mice. The reported data indicate sPLA2-IIA participation in murine osteoclast maturation, control of syncytium formation and resorbing activity, by mechanisms that may be both catalytically dependent and independent. Of note, these studies provide a more complete understanding of the still enigmatic osteoclast multinucleation process, a crucial step for bone-resorbing activity, uncovering the role of sPLA2-IIA interaction with a still unidentified receptor to regulate osteoclast fusion through p38 SAPK activation. This could pave the way for the design of specific inhibitors of sPLA2-IIA binding to interacting partners implicated in osteoclast syncytium formation.

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Role of human group IIA secreted phospholipase A2 in malaria pathophysiology: Insights from a transgenic mouse model

Cited by 6 publications

References 116 publications

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Modulation of immunity by the secreted phospholipase A₂ family

Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

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Role of human group IIA secreted phospholipase A2 in malaria pathophysiology: Insights from a transgenic mouse model

Cited by 6 publications

References 116 publications

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Modulation of immunity by the secreted phospholipase A2 family

Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

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Product

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Modulation of immunity by the secreted phospholipase A₂ family