Macrophage secretory phospholipase A2 group X enhances anti-inflammatory responses, promotes lipid accumulation, and contributes to aberrant lung pathology.
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 low-density 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-Delta12,14-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.
Departments of Molecular Genetics and Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands. d.curfs@gen.unimaas.nl
Daniëlle M J
DM
Curfs
Stijn A I
SA
Ghesquiere
Monique N
MN
Vergouwe
Ingeborg
I
van der Made
Marion J J
MJ
Gijbels
David R
DR
Greaves
J Sjef
JS
Verbeek
Marten H
MH
Hofker
Menno P J
MP
de Winther
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D054509:Group X Phospholipases A2 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000002:abnormalities / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D008055:Lipids; D008070:Lipopolysaccharides; D016753:Interleukin-10; C037112:9-deoxy-delta-9-prostaglandin D2; D054509:Group X Phospholipases A2; D015230:Prostaglandin D2