The Role of PKR on Modulating Neuroinflammation and Cognitive Dysfunctions in a Peripheral Inflammation Model

Abstract

AbstractBackgroundIncreasing lines of evidence have shown that systemic inflammation may contribute to neuroinflammation and accelerate the progression of neurodegenerative diseases. The double-stranded RNA-dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and the formation of inflammasomes. This study aims to study the role of PKR in regulating systemic inflammation-triggered neuroinflammation and cognitive dysfunctions.MethodsIn this three-part study, laparotomy was used as an experimental model to study neuroimmune responses triggered by systemic inflammation. In the first part, wild-type C57BL/6J and C57BL/6-Tg(CD68-EGFP)1Drg/J mice were randomly assigned to laparotomy under sevoflurane anesthesia or sevoflurane anesthesia alone as a control. The effects of systemic inflammation on neuroinflammation and cognitive function were examined. In the second part, PKR-/-mice were used to determine the role of PKR in regulating laparotomy-induced systemic inflammation, neuroinflammation and cognitive dysfunctions. For the third part, rAAV-DIO-PKR-K296R was injected intracerebroventricularly into the right lateral ventricle of ChAT-IRES-Cre-eGFP mice to inhibit PKR activation in cholinergic neurons. The effects of blocking PKR in cholinergic neurons on modulating glucose metabolism and cognition in the laparotomy model were examined.ResultsGenetic deletion of PKR in mice potently ameliorated the laparotomy-induced peripheral and neural inflammatory responses (downregulated pro-inflammatory cytokine expressions and activation of microglia), and cognitive dysfunctions. Inhibition of PKR in cholinergic neurons in mice could rescue the laparotomy-induced brain glucose hypometabolism and cognitive deficits.ConclusionsOur results suggested the critical role of PKR on modulating neuroinflammation and cognitive dysfunctions in a peripheral inflammation model. PKR could be a pharmacological target for treating systemic inflammation-induced neuroinflammation and cognitive deficits.