Abstract
Among the enzymes involved in the hydrolysis of membrane phospholipids, type-IIA secreted phospholipase A2 (sPLA2-IIA) plays a major role in the development of a number of inflammatory diseases. Indeed, this enzyme has been shown to release arachidonic acid, the precursor of pro-inflammatory eicosanoids, and to hydrolyze phospholipids of pulmonary surfactant. This hydrolysis, which alters the tensioactive properties of surfactant phospholipids, leading to alveolar collapse, plays a critical role in the pathogenesis of acute respiratory distress syndrome. sPLA2-IIA has also been shown to bind to specific receptors located on cell surface membranes, although the biological significance of this binding remains unclear. However, the most well-established biological role of sPLA2-IIA is related to its potent bactericidal properties compared to other sPLA2s. This bactericidal effect is due to the ability of sPLA2-IIA to bind to and penetrate the cell wall of bacteria, especially those of Gram-positive bacteria. This bactericidal function was highlighted in transgenic mice over-expressing human sPLA2-IIA (sPLA2-IIA Tg mice), which are more resistant to infection by Staphylococcus aureus than sPLA2-IIA–/– mice. This protective role was recently demonstrated for Bacillus anthracis, the etiological agent of anthrax. Indeed, sPLA2-IIA Tg mice are resistant to the fully virulent B. anthracis strains, in contrast to sPLA2-IIA–/– mice, which died rapidly after infection. Instillation of recombinant sPLA2-IIA protects sPLA2-IIA–/– mice from mortality caused by this bacterium. Nevertheless, our studies revealed that B. anthracis produces a toxin, known as lethal toxin, which downregulates sPLA2-IIA synthesis and secretion by alveolar macrophages (AM), leading to an almost complete loss of the bactericidal activity produced by these cells. These data clearly demonstrate that sPLA2-IIA might play a major role in host defense against anthrax. Conversely, this bacterium is able to disarm the host immune system, at least in part, through the inhibition of sPLA2-IIA expression by AM.