TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation

Significance The NLRP3 inflammasome is an innate sensor activated by signals released from pathogens or injured tissues. Activation of the NLRP3 inflammasome can be beneficial during infection and vaccination. Nonetheless, when NLRP3 activity is uncontrolled and chronic it becomes detrimental and contributes to inflammation-driven pathology in several diseases. Licensing mechanisms must exist that prevent unwanted NLRP3 inflammasome responses. Here, we characterize one such mechanism. We describe that TBK1 and IKKε, two closely related kinases activated upon TLR signaling, act as a novel OFF switch for the NLRP3 pathway. Using pharmacological and genetic approaches, we show that TBK1 and IKKε together limit the responses downstream of the NLRP3 inflammasome activation and work against the PP2A phosphatase ON switch to balance NLRP3 activity.