Proposed mechanism of extracellular Hsp70-mediated neurotoxic pro-inflammatory response in tissue after IR. The initial ischemic stress followed by reperfusion leads to the cell injury (necrosis) and the release of Hsp70. That same ischemic stress (increase in intracellular Ca2+) and reperfusion (increase in ATP (adenosine triphosphate)) mediate PKC activation. These two events are the necessary and sufficient conditions for activation of Tlr4 signaling and production of neurotoxic levels of pro-inflammatory factors such as Tnf. This pro-inflammatory response can trigger further tissue damage leading to increasing levels of extracellular Hsp70. Thus, a cycle may be repeated many times, which can result in significant tissue damage after IR. ATP, Hsp70, heat shock protein 70; IR, ischemic reperfusion; PKC, protein kinase C.