The role of microglia in ischemic preconditioning

Abstract

Ischemic preconditioning (IPC) is an experimental phenomenon in which a brief ischemic stimulus confers protection against a subsequent prolonged ischemic event. Initially thought to be due to mechanistic changes in neurons, our understanding of IPC has evolved to encompass a global reprogramming of the Central Nervous System (CNS) after transient ischemia/reperfusion that requires innate immune signaling pathways including Toll‐like receptors (TLRs) and Type I interferons. Microglia are the CNS resident neuroimmune cells that express these key innate immune receptors. Studies suggest that microglia are required for IPC‐mediated neuronal and axonal protection. Multiple paradigms targeting TLRs have converged on a distinctive Type I interferon response in microglia that is critical for preconditioning‐mediated protection against ischemia. These pathways can be targeted through administration of TLR agonists, cytokines including interferon‐β, and pharmaceutical agents that induce preconditioning through cross‐tolerance mechanisms. Transcriptomic analyses and single cell RNA studies point to specific gene expression signatures in microglia that functionally shift these mutable cells to an immunomodulatory or protective phenotype. Although there are technological challenges and gaps in knowledge to overcome, the targeting of specific molecular signaling pathways in microglia is a promising direction for development of novel and effective pharmacotherapies for stroke. Studies on preconditioning in animal models, including nonhuman primates, show promise as prophylactic preconditioning treatments for selected at risk patient populations. In addition, our growing understanding of the mechanisms of IPC‐mediated protection is identifying novel cellular and molecular targets for therapeutic interventions that could apply broadly to both acute stroke and chronic vascular cognitive impairment patients.

Sexually dimorphic microglia and ischemic stroke

“…83 Studies implicate TLR4 activation leads to a number of downstream events that are necessary for the establishment of IPC and the microglial response to damage. 82 Supporting this idea, studies have shown that aged mice have increased microglial activity after injection of IL-1β and IL-12 into the hippocampus. 85 This phenomenon is known as microglia priming and can make the microglia susceptible to secondary inflammatory stimulus leading to an exaggerated inflammatory response after CNS injury.…”

“…Microglia also play a role in ischemic preconditioning (IPC), which is protective against prolonged ischemic events. TLRs are some of the key signaling pathways in IPC reprogramming of the CNS . A study demonstrated that pretreatment with unmethylated CpG oligodeoxynucleotides (ODNs)—a ligand for Toll‐like receptor 9 (TLR9)—induces protection against ischemic brain damage in mice and nonhuman primates .…”

“…However, it has been determined that CpG‐ODN induced cerebral ischemia tolerance only in male mice, not in females, which indicates a sex difference . Studies implicate TLR4 activation leads to a number of downstream events that are necessary for the establishment of IPC and the microglial response to damage . Supporting this idea, studies have shown that aged mice have increased microglial activity after injection of IL‐1β and IL‐12 into the hippocampus .…”

“…TLRs are some of the key signaling pathways in IPC reprogramming of the CNS. 82 A study demonstrated that pretreatment with unmethylated CpG oligodeoxynucleotides (ODNs)-a ligand for Toll-like receptor 9 (TLR9)-induces protection against ischemic brain damage in mice and nonhuman primates. 83,84 However, it has been determined that CpG-ODN induced cerebral ischemia tolerance only in male mice, not in females, which indicates a sex difference.…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…Following a sublethal hypoxic-ischemic injury, activation of TLRs can cause a greater cerebral ischemic tolerance, a process called preconditioning. However, activation of TLRs after ischemia-induced tissue and cell injury can worsen tissue damage through the NF-kB signaling pathway [ 21 , 29 , 30 ]. TLRs and their downstream signaling molecules represent a relevant pharmacologic target for modulation of tolerance to an ischemic insult [ 31 ].…”