Turnover of oxidatively damaged nuclear proteins in BV-2 microglial cells is linked to their activation state by poly(ADP-ribose)polymerase

During neuroinflammation, activated microglial cells migrate to the sites of neuronal injury, phagocytose neighboring cells, and produce large amounts of oxygen free radicals, which might contribute to severe cell damage and death. It is interesting that microglial cells have withstood this cytotoxic action of free radicals, which indicates that there is an intracellular mechanism that apparently enables microglial cells to cope with such oxidative challenges. In this study, we investigated the capability of BV-2 murine microglial cells to cope with oxidatively damaged proteins by the proteasomal proteolytic system. To induce a highly activated state, we used the proinflammatory cytokine tumor necrosis factor-alpha, which acts as a priming signal for microglial superoxide radical production. We showed that activation of the nuclear enzyme poly(ADPribose)polymerase (PARP) enabled activated microglial cells to resist oxidative damage by an up-regulation of the nuclear proteasome. Activated microglial cells revealed an efficient recognition and degradation of oxidatively damaged proteins during an enhanced endogenous protein turnover. The impairment of PARP function by inhibitor or antisense experiments resulted in an accumulation of damaged proteins and subsequently cell death. In contrast, this was not the case in resting microglial cells. These findings demonstrate the crucial role of the PARP in microglial cell survival during activation and renders it a potential anti-inflammatory target.