Toll-Like Receptor Tolerance as a Mechanism for Neuroprotection

It has been discovered recently that Toll-like receptors (TLRs) are key mediators of tissue injury in response to stroke. This revelation has identified a new target critical to understanding the underlying mechanisms of stroke injury and potential therapies. Much of the interest in TLRs centers around their ability to self-regulate-a process commonly referred to as "tolerance," wherein prior exposure to low-level TLR activation induces protection against a subsequent challenge that would otherwise cause damage. This endogenous process has been exploited in the setting of stroke. Recent studies show that TLR pathways can be reprogrammed via prior exposure to TLR ligands, leading to decreased infarct size and improved neurological outcomes in response to ischemic injury. Efforts to understand the molecular mechanisms of TLR reprogramming have led to the identification of multiple routes of TLR regulation including inhibitors that target signaling mediators, microRNAs that suppress genes posttranscriptionally, and epigenetic changes in chromatin remodeling that affect global gene regulation. In this review, we discuss the role of TLRs in mediating injury due to stroke, evidence for TLR-preconditioning-induced TLR reprogramming in response to stroke, and possible mechanisms of TLR-induced neuroprotection.