Hypothermia Reduces but Hyperthermia Augments Microglial- and T Cell-Derived Release of Factors that Mediate Neuronal Cell Death

Abstract

Therapeutic hypothermia protects neurons after severe brain damage; however, the underlying mechanisms have yet to be fully elucidated. Activated microglia, which appear soon after the primary injury, release cytokines and nitric oxide（NO），known to damage neurons. T cells infiltrate the infarcted brain tissue within days of cerebral ischemia and play essential roles in exacerbating ischemic brain injury by producing inflammatory factors. Then, we examined how therapeutic hypothermia can prevent and brain hyperthermia can exacerbate secondary brain damage and demonstrated that the release of tumor necrosis factor（TNF）-α, interleukin（IL）-10, and NO from microglia, and that of IL-17 and granzyme B（GrB），a serine protease, from several T cell lineages is reduced by hypothermia but augmented by hyperthermia. The pathophysiological significance of these temperature-dependent changes in TNF-α, IL-10, NO, IL-17, and GrB levels in relation to hypothermic neuronal protection and hyperthermic neuronal injury was demonstrated by showing that all these molecules independently induce neuronal cell death in a concentration-dependent manner, in which the kinetics of concentration dependence was found to be proportional to that of the temperature-dependent changes in their production. These findings suggest that a decrease in TNF-α, IL-10, NO, IL-17, and GrB levels during hypothermia contributes to the direct protection of neurons, whereas an increase in their levels during hyperthermia contributes to direct injury of neurons.