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

• Published in: The Journal of biological chemistry Vol. 283; no. 31; pp. 21640 - 21648
• Main Authors: Curfs, Daniëlle M.J., Ghesquiere, Stijn A.I., Vergouwe, Monique N., van der Made, Ingeborg, Gijbels, Marion J.J., Greaves, David R., Verbeek, J. Sjef, Hofker, Marten H., de Winther, Menno P.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Cell Line; Cells, Cultured; Group X Phospholipases A2 - metabolism; Group X Phospholipases A2 - physiology; Humans; Interleukin-10 - metabolism; Lipids - chemistry; Lipopolysaccharides - metabolism; Lung - abnormalities; Lung - pathology; Macrophages - metabolism; Mice; Mice, Transgenic; Models, Biological; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M710584200

Secreted phospholipase A2 group X (sPLA2-X) is one of the most potent enzymes of the phospholipase A2 lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and low-density lipoproteins (LDL), has implicated sPLA2-X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA2-X enzyme activity in vitro and in vivo, by generating sPLA2-X-overexpressing macrophages and transgenic macrophage-specific sPLA2-X mice. Our results show that sPLA2-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 E2 (PGE2) and 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). Moreover, we found that overexpression of active sPLA2-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 sPLA2-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 sPLA2-X enzyme results in enhanced foam cell formation but reduced activation and inflammatory responses in macrophages in vitro. Interestingly, enhanced sPLA2-X activity in macrophages in vivo leads to fatal pulmonary defects, suggesting a crucial role for sPLA2-X in inflammatory lung disease.