Expression of phosphatidylserine receptor and down-regulation of pro-inflammatory molecule production by its natural ligand in rat microglial cultures

Exposure of phosphatidylserine (PS), an aminophospholipid normally sequestered in the inner leaflet of plasma membrane, is one of the crucial steps in the recognition and ingestion of apoptotic cells by macrophages. The recognition of PS on apoptotic cells by peripheral macrophages is mediated by a phosphatidylserine-specific receptor (PtdSerR), which has recently been cloned. In spite of the important role of apoptosis in the CNS, the process of apoptotic neuron recognition by microglia is poorly understood. Because recent studies suggest that engagement of PS with a not yet characterized microglial receptor is necessary for apoptotic neuron uptake, we investigated the expression of PtdSer-R and its functional role in neonatal rat brain microglial cultures. Semi-quantitative RT-PCR analysis revealed that PtdSerR mRNA was detectable in unstimulated cultures and enhanced in LPS activated microglia. The presence of PS-liposomes strongly reduced the release of pro-inflammatory molecules such as nitric oxide, interleukin-1beta. and tumor necrosis factor-alpha by LPS-activated microglia. At variance, the immunoregulatory cytokines interleukin-10 and transforming growth factor-beta1 were moderately decreased or unaffected. The activity of PS-liposomes was mimicked by the PS head group phospho-L-serine, but not by phosphatidylcholine-containing liposomes. Our data suggest that, as for peripheral macrophages, PS through its receptor can modulate microglial activation toward an anti-inflammatory phenotype.