The protein kinase R as a repressor of inflammasome activity

Inflammasomes are a key component of cytosolic surveillance. They are multi-protein complexes that regulate maturation of the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and drive cell death via pyroptosis. As well as responding to exogenous, pathogen-associated molecules, the inflammasomes also respond to endogenous signals, making these sensors prime mediators of inflammation. Since their groundbreaking description a decade ago, there has been an intense effort to discover the mechanisms that regulate the activity of inflammasomes, to enable therapeutic control of inflammation. Towards this, it has recently been reported that the antiviral protein kinase R (PKR) promotes inflammasome activity, endorsing the use of pharmacological inhibition of PKR to treat inflammation. However, this conclusion is contradicted by our findings that PKR has variable effects on the inflammasomes, even repressing their activity in specific instances. In these instances, inhibiting the activity of PKR could be counterproductive and even detrimental. Here we present data contradicting a pro-inflammatory function for PKR and identifying the mechanism by the kinase represses activity of the NLRP3 inflammasome.