微膠細胞(microglia)為中樞神經中相當於免疫系統的巨噬細胞，能偵測神經系統中微環境的變化來引起類似免疫反應，並且擁有吞噬細胞/組織碎片的活性。微膠細胞的功能對於損傷的中樞神經系統組織/系統修復重建而言是非常重要的。ATP在免疫反應及神經系統功能中為重要的調控分子。神經系統受到損傷導致細胞損傷和死亡，此時ATP從損傷區的神經元細胞和活化的神經膠細胞被大量釋放，並透過活化P2受體(離子通道型的P2XR和G蛋白偶合型的的P2YR)調控微膠細胞的免疫細胞活性。本研究將初級微膠細胞與高濃度ATP或P2X7R促效劑(BzATP)共同培養30分鐘，發現細胞型態發生改變，並且顯著抑制微膠細胞的吞噬活性。以P2X7R拮抗劑(oxATP與BBG)抑制微膠細胞P2X7R的功能和利用慢病毒基因載體(lentiviral-mediated shRNA)降低微膠細胞P2X7R的基因表現，證實ATP降低微膠細胞的吞噬能力是透過引發P2X7R的活化，此調控機制是與P2X7R誘發胞內鈣離子濃度增加無關。
先前本實驗室植入C6 glioma cells建立腦膠質瘤動物模式實驗中發現，在植入第3天和7天發現ED1+微膠細胞/巨噬細胞和Iba1+微膠細胞累積於腦腫瘤區域。雙重免疫螢光染色結果顯示累積在腦腫瘤區域的微膠細胞/巨噬細胞有macrophage inflammatory protein-1α (MIP-1α)和monocyte chemoattractant protein-1 (MCP-1)的表現。接續的實驗發現高濃度ATP處理微膠細胞會增加其胞內MIP-1α和MCP-1的表現量。結果證實BzATP的處理亦增加微膠細胞內MIP-1α和MCP-1生成量，而且調控機製為P2X7R誘發胞內鈣離子濃度增加的訊息傳遞途徑有關。在動物實驗中，C6 glioma cells和oxATP共同注射入腦皮質區，雖然Iba1+微膠細胞仍舊大量累積於腦腫瘤區域，但是表現MIP-1α和MCP-1的微膠細胞/吞噬細胞顯著減少。而且，oxATP的注射能有效抑制腦腫瘤的生長。
綜合上述細胞與動物實驗結果，推測中樞神經系統損傷之後產生高量的ATP可以透過活化P2X7R誘發與非鈣離子主導的訊息傳遞路徑(calcium-independent)抑制微膠細胞的吞噬活性，導致清除受傷組織細胞殘骸碎片的效力低，進而阻礙組織的修復。另外，腦腫瘤區域高濃度的ATP也可能透過P2X7R活化與鈣離子主導(calcium-dependent)訊息傳遞途徑，增加微膠細胞/巨噬細胞內MIP-1α和MCP-1的表現量。因此，藉由阻斷P2X7R的活化，可以維持微膠細胞的吞噬活性，助益神經組織的修復；並且減低累積在腦膠質瘤內微膠細胞MIP-1α和MCP-1的表現量而抑制腦腫瘤的生長。

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.

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