Hypothermic and hyperthermic effects on microglial regulation through cross-talk between activation of toll-like receptor and hypoxia-ischemia

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Activated microglia produce neurotoxic factors, including pro-inflammatory cytokines and nitric oxide (NO), in response to neuronal destruction. Hence, the suppression of the microglial release of these factors may contribute to the neuroprotective effects of therapeutic hypothermia. I examined the effects of hypothermic culture on the production of pro- and anti-inflammatory cytokines and NO in ex vivomicroglia that were derived from mice with hypoxic-ischemic (HI) brain injury, through the stimulation of toll-like receptors (TLRs) that play significant roles in the pathological processes underlying sterile central nervous system injury. Microglia were isolated from HI brain-injured mice and then cultured with TLR2 and TLR4 agonists at 33°C and 37°C. As a result, compared with 37°C, hypothermia (33°C) reduced the production of TNF-α at 6 h and IL-10 and NO at 48 h. In a clinically relevant setting using TLR-activated microglia that were derived from mice with HI brain injury, hypothermia reduced the production of TNF-α, IL-10, and NO in a time-dependent manner, supporting the idea that neuroprotection conferred by therapeutic hypothermia could be related to attenuation of both early-phase TNF-α and late-phase IL-10 and NO released from microglia. In particular, this mechanism may be responsible for HI brain injury.