Secreted phospholipase A 2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

Background: activation of microglia,the primary component of the innate immune response in the brain,is a hallmark of neuroinflammation in neurodegenerative disorders,including alzheimer's disease (ad) and other pathological conditions such as stroke or cns infection. in response to a variety of insults,microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury,and play an important role in the recognition,engulfment,and clearance of apoptotic cells and/or invading microbes. secreted phospholipase a 2-iia (spla 2-iia),an enzyme that interacts with cells involved in the systemic immune/inflammatory response,has been found up-regulated in the cerebrospinal fluid and brain of ad patients. however,despite several approaches,its functions in mediating cns inflammation remain unknown. in the present study,the role of spla 2-iia was examined by investigating its direct effects on microglial cells.methods: primary and immortalized microglial cells were stimulated by spla 2-iia in order to characterize the cytokine-like actions of the phospholipase. the hallmarks of activated microglia analyzed include: mitogenic response,phagocytic capabilities and induction of inflammatory mediators. in addition,we studied several of the potential molecular mechanisms involved in those events.results: the direct exposure of microglial cells to spla 2-iia stimulated,in a time- and dose-dependent manner,their phagocytic and proliferative capabilities. spla 2-iia also triggered the synthesis of the inflammatory proteins cox-2 and tnfα. in addition,egfr phosphorylation and shedding of the membrane-anchored heparin-binding egf-like growth factor (pro-hb-egf) ectodomain,as well as a rapid activation/phosphorylation of the classical survival proteins erk,p70s6k and rs6 were induced upon spla 2-iia treatment. we further demonstrated that the presence of an egfr inhibitor (ag1478),a matrix metalloproteinase inhibitor (gm6001),an adam inhibitor (tapi-1),and a hb-egf neutralizing antibody abrogated the phenotype of activated microglia induced by the spla 2-iia.conclusion: these results support the hypothesis that spla 2-iia may act as a potent modulator of microglial functions through its ability to induce egfr transactivation and hb-egf release. accordingly,pharmacological modulation of egfr might be a useful tool for treating neuroinflammatory diseases characterized by spla 2-iia accumulation. © 2012 martín et al.; licensee biomed central ltd.