Phospholipase A2IVα Regulates Phagocytosis Independent of Its Enzymatic Activity

Zizza, Pasquale; Iurisci, Cristiano; Bonazzi, Matteo; Cossart, Pascale; Leslie, Christina C.; Corda, Daniela; Mariggiò, Stefania

doi:10.1074/jbc.m111.309419

Cited by 21 publications

(43 citation statements)

References 60 publications

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“…In this regard, cPLA 2 a, the first rate-limiting enzyme for eicosanoid synthesis, was found to translocate to the phagosome to regulate phagocytosis at various steps, some of which may depend on eicosanoid synthesis, whereas others may not (49,82). We detected a rather modest production of eicosanoids in IL-4-treated cells that did not change whether sPLA 2 -Vdeficient or normal cells were used.…”

Section: Discussionmentioning

confidence: 54%

“…Alternatively, the possibility that loss of function in sPLA 2 -V-depleted macrophages may, in part, be unrelated to lysophospholipids cannot be ruled out if the enzyme is also exerting noncatalytical functions in the cells. In this regard, recent data showed that cPLA 2 a translocation to nascent phagosomes in murine macrophages takes place in a manner that is independent of its enzymatic activity (82).…”

Section: Discussionmentioning

confidence: 99%

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Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-γ plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-γ plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4–treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4–treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V–derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V–deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4–treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4–treated human macrophages and provide evidence that sPLA2-V–derived LPE is involved in the process.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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“…These functions would be lost if inhibition were accomplished by genetic approaches, but not if chemical inhibitors were used. In this regard, recent data have shown that, during phagocytosis, cPLA 2 a translocates to the site of nascent phagosomes to modulate the phagocytic process in a manner that is independent of its enzymatic activity (66). Of course, the use of chemical inhibitors has its own issues, such as the lack of specificity, and we acknowledge this as a limitation of the current study.…”

Section: Discussionmentioning

confidence: 64%

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Gil-de-Gómez

Astudillo

Guijas

et al. 2014

The Journal of Immunology

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Phospholipase A2s generate lipid mediators that constitute an important component of the integrated response of macrophages to stimuli of the innate immune response. Because these cells contain multiple phospholipase A2 forms, the challenge is to elucidate the roles that each of these forms plays in regulating normal cellular processes and in disease pathogenesis. A major issue is to precisely determine the phospholipid substrates that these enzymes use for generating lipid mediators. There is compelling evidence that group IVA cytosolic phospholipase A2 (cPLA2α) targets arachidonic acid–containing phospholipids but the role of the other cytosolic enzyme present in macrophages, the Ca2+-independent group VIA phospholipase A2 (iPLA2β) has not been clearly defined. We applied mass spectrometry–based lipid profiling to study the substrate specificities of these two enzymes during inflammatory activation of macrophages with zymosan. Using selective inhibitors, we find that, contrary to cPLA2α, iPLA2β spares arachidonate-containing phospholipids and hydrolyzes only those that do not contain arachidonate. Analyses of the lysophospholipids generated during activation reveal that one of the major species produced, palmitoyl-glycerophosphocholine, is generated by iPLA2β, with minimal or no involvement of cPLA2α. The other major species produced, stearoyl-glycerophosphocholine, is generated primarily by cPLA2α. Collectively, these findings suggest that cPLA2α and iPLA2β act on different phospholipids during zymosan stimulation of macrophages and that iPLA2β shows a hitherto unrecognized preference for choline phospholipids containing palmitic acid at the sn-1 position that could be exploited for the design of selective inhibitors of this enzyme with therapeutic potential.

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“…Besides its role in eicosanoid biosynthesis, cPLA 2 ␣ is selectively activated upon Fc receptor (FcR)-mediated phagocytosis in macrophages, where it rapidly translocates to the nascent phagosome ( 23 ). Unexpectedly, however, it was shown that membrane binding by the isolated C2 domain of cPLA 2 ␣ was suffi cient to induce phagosome formation ( 23 ), suggesting that the C2 domain alone has membrane binding activity that regulates phagocytosis.…”

Section: Methodsmentioning

confidence: 99%

“…Unexpectedly, however, it was shown that membrane binding by the isolated C2 domain of cPLA 2 ␣ was suffi cient to induce phagosome formation ( 23 ), suggesting that the C2 domain alone has membrane binding activity that regulates phagocytosis. This was further verifi ed with a mutation in the C2 domain, D43N, which abrogates Ca 2+ -binding and could not rescue phagocytosis ( 23 ).…”

Section: Methodsmentioning

confidence: 99%

C2 domain membrane penetration by group IVA cytosolic phospholipase A2 induces membrane curvature changes

Ward

Ropa

Adu-Gyamfi

et al. 2012

Journal of Lipid Research

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Phospholipase A2IVα Regulates Phagocytosis Independent of Its Enzymatic Activity

Cited by 21 publications

References 60 publications

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

C2 domain membrane penetration by group IVA cytosolic phospholipase A2 induces membrane curvature changes

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