Macrophage Secretory Phospholipase A2 Group X Enhances Anti-inflammatory Responses, Promotes Lipid Accumulation, and Contributes to Aberrant Lung Pathology

Abstract

Secreted phospholipase A2 group X (sPLA 2 -X) is one of the most potent enzymes of the phospholipase A 2 lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and lowdensity lipoproteins (LDL), has implicated sPLA 2 -X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA 2 -X enzyme activity in vitro and in vivo, by generating sPLA 2 -X-overexpressing macrophages and transgenic macrophage-specific sPLA 2 -X mice. Our results show that sPLA 2 -X expression inhibits macrophage activation and inflammatory responses upon stimulation, characterized by reduced cell adhesion and nitric oxide production, a decrease in tumor necrosis factor (TNF), and an increase in interleukin (IL)-10. These effects were mediated by an increase in IL-6, and enhanced production of prostaglandin E 2 (PGE 2 ) and 15-deoxy-⌬12,14-prostaglandin J 2 (PGJ 2 ). Moreover, we found that overexpression of active sPLA 2 -X in macrophages strongly increases foam cell formation upon incubation with native LDL but also oxidized LDL (oxLDL), which is mediated by enhanced expression of scavenger receptor CD36. Transgenic sPLA 2 -X mice died neonatally because of severe lung pathology characterized by interstitial pneumonia with massive granulocyte and surfactant-laden macrophage infiltration. We conclude that overexpression of the active sPLA 2 -X enzyme results in enhanced foam cell formation but reduced activation and inflammatory responses in macrophages in vitro. Interestingly, enhanced sPLA 2 -X activity in macrophages in vivo leads to fatal pulmonary defects, suggesting a crucial role for sPLA 2 -X in inflammatory lung disease.

Analyses of Group III Secreted Phospholipase A2 Transgenic Mice Reveal Potential Participation of This Enzyme in Plasma Lipoprotein Modification, Macrophage Foam Cell Formation, and Atherosclerosis

“…We also incubated peritoneal macrophages from PLA2G10 Tg mice (22) with LDL and found that these cells also accumulated oil red O-stained lipid droplets (Fig. 6D), confirming that PLA2G10-exposed LDL facilitates macrophage foam cell formation, as reported previously (23,31,34). After treatment with Ac-LDL, formation of foam cells from macrophages of all genotypes was obvious (Fig.…”

“…In our ongoing effort to gain new insights into the in vivo functions of sPLA 2 enzymes, in this study we established and analyzed Tg mice for PLA2G3, an atypical mammalian sPLA 2 structurally more similar to bee venom PLA 2 than to other mammalian sPLA 2 s. PLA2G3 Tg mice did not display noticeable phenotypic changes in the skin, which is profoundly affected in PLA2G2A mice (24), or lung, whose architecture is disrupted in PLA2G5 Tg mice (22) and macrophage-specific PLA2G10 Tg mice (23), suggesting that phospholipids in mouse skin and lung surfactant may not be main targets for PLA2G3 in vivo. However, we have obtained evidence that PLA2G3 can target phospholipids in plasma lipoproteins in vivo, leading to a decrease in HDL and an increase in modified and aggregated LDL, which are risk factors for atherosclerosis.…”

Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma

“…Further study using model systems with selective PLa2g10 deficiency in epithelial cells and macrophages will be needed to resolve the relative importance of each of these cell types in animal models, because the development of airway inflammation and AHR is impaired with global PLa2g10 deficiency (21,22). Although transgenic expression of full-length PLA2G10 in mice is not associated with pathology in the absence of inflammation (40), the transgenic expression of active PLA2G10 without the propeptide sequence in macrophages causes significant lung dysfunction related to the degradation of surfactant phospholipids (41). Thus, macrophage expression of PLA2G10 could alternatively be an important source of sPLA 2 -X in the airways.…”

Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

“…GX KO mice exhibit significantly reduced myocardial infarct size in response to ischemia/reperfusion injury, which has been attributed to attenuated neutrophil cytotoxic activities (18). Transgenic macrophage-specific expression of the mature form of human GX sPLA 2 results in fatal pulmonary defects in mice suggesting an involvement of GX sPLA 2 in inflammatory lung diseases (19).…”