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Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead cells must be quickly removed to avoid the further toxic effects they exert in the pa-renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artiifcial phagocytic targetsin vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser-vation and quantiifcation of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. hTese parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inlfammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to ifnd and engulf apoptotic cells, resulting in accumulation of debris and inlfammation. Herein, we advocate that the effciency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro-logical disorders, in order to determine the extent to which it contributes to apoptosis and inlfammation found in these conditions. Finally, our ifndings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inlfammation, and accelerate recovery in brain diseases.