Fig. 2. Regulation of the NLRP3 inflammasome activation.

Activation of the NLRP3 inflammasome involves both the priming and activation steps. In the priming step (Signal 1), inflammatory triggers such as TLR4 agonist LPS induces the NF-κB-mediated expression of NLRP3, pro-IL-1β and pro-caspase-1. In the activation step, diverse PAMPs and DAMPs trigger the NLRP3 inflammasome assembly though unifying events such as ion flux, mitochondrial dysfunction and ROS formation. Regulation of the NLRP3 inflammasome activation can occur at the post-transcriptional and post-translational levels. MicroRNAs (e.g., MiR-223, MiR-22, MiR-7, and MiR-30e) inhibit the NLRP3 activity by targeting its UTR binding sites, and long non-coding RNAs (e.g., ANRIL, MALAT1, Neat 1, and Gm15441) can either promote or inhibit the inflammasome signaling. The post-translational modifications at different sites and domains of NLRP3 protein include phosphorylation, dephosphorylation, ubiquitination, de-ubiquitination, and S-nitrosylation. Many molecules such as BCAP, IRGM, and DDX3X can interfere the assembly of NLRP3, ASC, and procaspase-1. Other negative regulatory molecules inhibit the inflammasome activation by targeting the K⁺ efflux (e.g., BHB), cytosolic Ca²⁺ (e.g., TMEM176B), mitochondrial function (e.g., macrophage CGI-58, IL-10, and NO).