P2X7 receptor mediates microglia phagocytosis and chemokine production

• Main Authors: Kuan-MinFang, 方冠旻
• Other Authors: Shun-Fen Tzeng
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/82807819180002823036

博士 === 國立成功大學 === 生命科學系碩博士班 === 99 === Microglia, CNS-resident macrophages, are considered as a sensor to detect the change of CNS microenvironment and exert immune-like functions in protecting the CNS from injury and invading pathogens. These cells are rapidly activated and engulf degenerating cellular fragments in injured CNS, indicating that they are essential to tissue/system modeling in the injured CNS. ATP, an important intercellular regulator in the immune and nervous systems, is released primarily from injured neural cells and glial cells at the lesion site and glioma cells. ATP is known to mediate microglial activity through the activation of P2 purinergic receptors (ionotropic P2XR and G-protein coupled P2YR). To examine whether ATP mediates microglia function, in vitro and in vitro experiments were conducted in my study. The in vitro study indicated that exposure to a high concentration of ATP for 30 min rapidly induces changes of the microglial cytoskeleton and significantly attenuates microglial phagocytosis. A pharmacological approach and knockdown of P2X7R expression by lentiviral-mediated shRNA interference showed that ATP-induced inhibition of microglial phagocytotic activity was due to P2X7R-induced Ca2+-independent signaling pathway. Previously, we have found that Iba1+ microglia and ED1+ microglia/macrophages accumulated in the tumor at 3 day after injection of C6 glioma cells into the rat cerebral cortex (dpi) and at 7 dpi. ED1+ microglia/macrophages or Iba1+ microglia in the glioma were also co-localized to macrophage inflammatory protein-1α (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1) expressing cells. Here, we found that application of ATP increased the release of MIP-1α and MCP-1 in primary microglia. The further study demonstrated that BzATP-induced production of MIP-1α and MCP-1 levels was due to P2X7R activation and Ca2+-dependent regulation. Co-administration with C6 glioma cells and oxATP into the rat cerebral cortex resulted in a reduction of MIP-1α and MCP-1 expressing microglia/macrophages. In addition, the application of oxATP effectively suppressed the growth of C6-induced glioma tumor. Together, based on the results from in vivo and in vitro studies, we suggest that exposure to ATP for a short-term period may cause insufficient clearance of tissue debris by microglia through P2X7R activation after CNS injury. A massive amount of ATP molecules released in the injured CNS may act as the regulator with P2X7R signaling to increases MIP-1α and MCP-1 expression in tumor-infiltrating microglia/macrophages. Thus, blockade of this receptor may not only preserve the phagocytosis of microglia and facilitate CNS tissue repair, but also inhibit tumor growth by the reduction of MIP-1α and MCP-1 expressing microglia in the tumor site.