Roles of inflammasomes in viral myocarditis

Figures

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  Figure 1. The mechanism of inflammasome activation. (1) The NLRP3 inflammasome activation. The activation of the NLRP3 inflammasome requires two steps of stimuli. The first signals are mainly PAMPs or DAMPs, interacting with the PRRs and activating the NF-κB pathway, thus promoting the transcription of NLRP3, pro-IL-1β and pro-IL-18. The second signals promote the assembly and oligomerization of the NLRP3 inflammasome. The efflux of K+, influx of Na+, mobilization of Ca2+ (from ER and extracellular), mtROS, mtDNA, lysosomal leakage of H+ and cathepsin B facilitate the assembly of NLRP3, ASC, and pro-caspase-1. The efflux of Cl- facilitates the NEK7 attachment and thus the oligomerization. (2) The CARD8 inflammasome activation. The PAMPs induce the degradation of CARD8 sensor in proteasome and facilitate the release of CARD-UPA domain, which recruits pro-caspase-1 and results in the formation of CARD8 inflammasome. (3) The caspase-11 inflammasome activation. Under the stimulation of LPS, the caspase-11 inflammasome is formed, gains proteolytic activity, and cleave. (4) The AIM2 inflammasome. The AIM2 senses the dsDNA and then recruits the ASC and pro-caspase-1, facilitating the assembly and…

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  Figure 2. Activation and effect of inflammasome pathway in VMC induced by CVB3. (1) CARD8 inflammasome pathway. The 2A and 3C proteases of CVB3 promote the cleavage of CARD8 to form the CARD8 inflammasome, which provides a platform for the maturation of pro-caspase-1. Caspase-1 cleaves GSDMD, and the transfer of the GSDMD N-terminal fragment to the cell membrane increases the permeability of the cell membrane, thereby promoting the release of replication-generated CVB3. (2) NLRP3 inflammasome pathway. CVB3 is recognized by NOD2, activating the NF-κB pathway, leading to the transcription of NLRP3, pro-IL-1 and pro-IL-18. CVB3-induced NLRP3 inflammasome activation in VMC is mediated by potassium efflux, release of cathepsin B caused by lysosomal damage, and ROS and mitochondrial dysfunction due to the transfer of calpain-1 to mitochondria. The NLRP3 inflammasome promotes the maturation of pro-IL-1β and pro-IL-18 and the cleavage of GSDMD. IL-1β plays a significant role in the development of VMC. MicroRNAs, including miR-15/223, are also involved. MiR-15 is up-regulated to repress NLRX1, while miR-223 is down-regulated to elevate the TRAF6, both contributing to the NLRP3 inflammasome…