Toll-like receptor signaling in endogenous neuroprotection and stroke

Stroke and other cerebral vascular diseases are a leading cause of morbidity and mortality in the United States. Despite intensive research to identify interventions that lessen cerebrovascular injury, no major therapies exist. Development of stroke prophylaxis involves an understanding of the mechanisms of damage following cerebral ischemia, and elucidation of the endogenous mechanisms that combat further brain injury. Toll-like receptors (TLRs) are critical components of the innate immune system that have been shown recently to mediate ischemic injury. Paradoxically, TLR ligands administered systemically induce a state of tolerance to subsequent ischemic injury. Herein we suggest that stimulation of TLRs prior to ischemia reprograms TLR signaling that occurs following ischemic injury. Such reprogramming leads to suppressed expression of pro-inflammatory molecules and enhanced expression of numerous anti-inflammatory mediators that collectively confer robust neuroprotection. Our findings indicate that numerous preconditioning stimuli lead to TLR activation, an event that occurs prior to ischemia and ultimately leads to TLR reprogramming. Thus genomic reprogramming of TLR signaling may be a unifying principle of tolerance to cerebral ischemia.