Secreted phospholipase A2 regulates intercellular communications by coordinating extracellular phospholipid metabolism

Abstract

Lipids play fundamental roles in life. In essence, "phospholipase A2" (PLA2) indicates a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes that possess PLA2 or related lipid-metabolizing activities have been identified in mammals and are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. Among the PLA2 superfamily, the secreted PLA2 (sPLA2) family contains 11 isoforms in mammals, each of which has unique substrate specificity and tissue/cellular distributions. Recent studies using gene-manipulated (knockout and/or transgenic) mice for a full set of sPLA2s have revealed their diverse roles in immunity, metabolism, and other biological events. Application of mass spectrometric lipidomics to these mice has allowed the identification of target substrates and products of individual sPLA2s in tissue microenvironments. In principle, sPLA2s hydrolyze extracellular phospholipids such as those in extracellular vesicles, microbes, lipoproteins, surfactants, and ingested foods, as well as phospholipids in the plasma membrane of activated or damaged cells, thereby exacerbating or ameliorating various diseases. The actions of sPLA2s are dependent on, or independent of, the generation of free fatty acids, lysophospholipids, or their metabolites (lipid mediators) according to pathophysiological contexts. In this review, I will make an overview of recent understanding of the unexplored immunoregulatory roles of sPLA2s and their underlying lipid pathways, especially focusing on their unique actions on extracellular vesicles, activated/damaged cells, and gut microbiota.

Keywords: extracellular vesicle; lipid mediator; lipidomics; metabolism; microbiome.

Graphical Abstract

Figure 1.

Classification and functions of mammalian sPLA₂s. Classical sPLA₂s (group I/II/V/X) are closely related, low-molecular-weight (14−19 kDa) enzymes with a His/Asp catalytic dyad and a highly conserved Ca²⁺-binding loop. They have six to eight conserved disulfide bonds that ensure their high structural stability. The genes for sPLA₂-IIA, -IIC (present in rodents, but a pseudogene in human), -IID, -IIE, -IIF, and -V are clustered on the same chromosome locus and therefore often referred to as the group II subfamily. sPLA₂-IB has seven disulfide bonds, including a group I-specific Cys¹¹–Cys⁷⁷ disulfide, a unique five amino acid insertion termed the pancreatic loop, and an N-terminal propeptide that is proteolytically cleaved for its activation. Typical group II sPLA₂s (sPLA₂-IIA, -IID, and -IIE) have seven disulfide bonds, including a group II-specific disulfide linking Cys⁵⁰ with the C-terminal Cys in a C-terminal extension. sPLA₂-IIC has an extra disulfide bond in a unique sequence in the middle region. sPLA₂-IIF possesses a long C-terminal extension with a unique free Cys residue. sPLA₂-V does not have the group I- and group II-specific disulfides and the group II-specific C-terminal extension. sPLA₂-X possesses both group I- and group II-specific disulfides and an N-terminal propeptide. Atypical sPLA₂s in the group III and XII branches share homology with the classical sPLA₂s only in the catalytic site and Ca²⁺-binding loop. sPLA₂-III is an unusually large protein (55 kDa) consisting of a central sPLA₂ domain with 10 cysteines, flanked with unique N- and C-terminal domains that are proteolytically removed during protein maturation. sPLA₂-XIIA and -XIIB (catalytically inactive) are 19-kDa proteins with the lowest homology with other sPLA₂s. Immunological, metabolic, and other functions of individual sPLA₂s described in this review are briefly summarized on the right. For details, please see the text. VLDL, very low-density lipoprotein.

Figure 2.

Paracrine regulation of immunological responses by sPLA ₂ s via lipolytic modification of EVs. (A) In rheumatoid arthritis, sPLA₂-IIA secreted from synovial cells or platelets attacks platelet-derived EVs to generate 12-HETE and DAMPs (e.g. mitochondrial DNA and oxidized lysophospholipids), which activate neutrophils to amplify sterile inflammation. (B) In EBV-induced B-cell lymphoma, sPLA₂-X supplied by TAMs targets lymphoma-derived EVs to generate LPA, which increases IL-10 secretion by TAMs to exaggerate tumor development. (C) sPLA₂-III secreted from mast cells hydrolyzes mast cell-derived EVs to generate LPA, which acts on adjacent fibroblasts to increase PGD₂ and IL-33 that facilitate mast cell maturation. (D) In the context of Th17-driven pathology, sPLA₂-XIIA secreted from activated T cells hydrolyzes T cell-derived EVs to generate LPE and LPA, which assist the differentiation and expansion of pathogenic Th17 cells. For details, please see the text.

Figure 3.

Regulation of immunological responses by sPLA ₂ s via modification of the gut microbiota. (A) sPLA₂-IIA secreted from intestinal Paneth cells modifies the gut microbiota through its bactericidal activity, thereby offering variable systemic effects. (B) A high-fat diet causes dysbiosis in the gastrointestinal tract, leading to local and systemic inflammation toward metabolic complications. sPLA₂-X secreted from the colonic epithelium releases ω3 PUFAs from host membranes, which can protect against diet-induced colonic inflammation and increase “good” bacteria. Unique lipids produced by these bacteria, including SCFAs (acetate, propionate, and butylate) as well as LA-derived HYA (10-hydroxy-cis-12-octadecenoic acid) and branched-chain fatty acids, including FAHFAs (fatty acid esters of hydroxy fatty acids) and AAHFAs (acyl α-hydroxyl fatty acids), have beneficial effects on systemic immunity and metabolism. For details, please see the text. PAMPs, pattern-associated molecular patterns.