Abstract
Therapeutic hypothermia protects neurons after injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in the pathogenesis of sterile CNS injury. To elucidate the possible mechanisms involved in the neuroprotective effect of therapeutic hypothermia, we examined the effects of hypothermic culture on TLR3-activated microglial release of interferon (IFN)-β and nitric oxide (NO), which are known to be associated with neuronal cell death. When rat or mouse microglia were cultured under conditions of hypothermia (33°C) and normothermia (37°C) with a TLR3 agonist, polyinosinic-polycytidylic acid, the production of IFN-β and NO in TLR3-activated microglia at 48 h was decreased by hypothermia compared with that by normothermia. In addition, exposure to recombinant IFN-β and sodium nitroprusside, an NO donor, caused death of rat neuronal pheochromocytoma PC12 cells in a concentration-dependent manner after 24 h. Taken together, these results suggest that the attenuation of microglial production of IFN-β and NO by therapeutic hypothermia leads to the inhibition of neuronal cell death.
Highlights
Toll-like receptors (TLRs) are major sensors of pathogenassociated molecular patterns (PAMPs) that mediate innate immunity and are involved in adaptive immune responses [1]
Our study shows that the production of IFN-β and nitric oxide (NO) by microglia was reduced when TLR3 signaling was activated by poly(I:C) under hypothermic culture conditions
We demonstrated that hypothermia reduced the production of IFN-β and NO by microglia expressing activated TLR3 and that these factors induced neuronal cell death
Summary
Toll-like receptors (TLRs) are major sensors of pathogenassociated molecular patterns (PAMPs) that mediate innate immunity and are involved in adaptive immune responses [1]. Production and release by damaged cells of molecules that are abnormally expressed or whose structures are altered can stimulate the activity of TLRs [2, 3] Under these conditions, these molecules are recognized as damage- or danger-associated molecular patterns that trigger immediate responses or enhance reactions to tissue injury and inflammation [3,4,5]. Dying CNS cells release HSP60 that binds to microglia, which in turn secrete neurotoxic nitric oxide (NO) These data provided the first evidence for an endogenous pathway that may be common to many forms of neuronal injury and that bidirectionally links CNS inflammation with neurodegeneration.
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