Traumatic brain injury (TBI) induces activation of microglia, the immune effector cells of the brain. The role of microglia in TBI is one of double-edged sword, having both neuroprotective and neurodegenerative effects. Therefore, a treatment goal would be to minimize negative, neurotoxic microglial actions while maximizing neuroprotection. Dissection of microglial interactions with other brain cell types and identification of biochemical pathways involved in microglial activation after TBI is difficult to accomplish in vivo. Many of the current models of in vitro microglial injury do not reproduce the major component of TBI, that being tissue strain or stretch. The goal of this proposal is to examine the signal transduction pathways responsible for TBI-induced microglial activation and determine the consequences of activation on neuronal injury, using a well-characterized in vitro stretch-injury model. Our recent studies demonstrate that microglia are not directly activated by stretch injury, but are activated by soluble factors released from stretch-injured astrocytes. Activated microglia had morphological alterations, increased arachidonic acid release, and enhanced intracellular calcium signaling consistent with macrophage activation. For the first time, we have identified upregulation of a glutamate-mediated calcium-signaling pathway in activated microglia, which may constitute a signaling network between microglia and injured astrocytes and neurons. We have also found that stretch-injured astrocytes and severely injured neurons release ATP into the extracellular space. We hypothesize that glutamate and ATP released by traumatically injured astrocytes and neurons initiates microglial chemotaxis activation. In the present proposal, we will continue to dissect the signaling pathways involved in stretch-induced microglial activation by examining arachidonic acid release, glutamate-mediated calcium signaling, morphological changes, proliferation, major histocompatibility antigen expression, phagocytosis, and chemotaxis. We will also determine the mechanisms through which stretch-activated microglia alter neuronal calcium signaling or exert neurotoxic effects. Using inhibitors of the arachidonic acid cascade, calcium signaling, purinergic and glutamatergic receptors, we will attempt to counteract microglial neurotoxicity. In vitro dissection of the mechanisms involved in the neuroprotection and neurotoxicity of microglia after trauma could permit the development of more effective strategies aimed at reduction of secondary injury after TBI by shifting the balance of microglial effects from neurotoxic to neuroprotective.
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