Cross-regulation between the IL-1β/IL-18 processing inflammasome and other inflammatory cytokines

Abstract

The inflammasome-forming NLRs are well characterized members of a protein complex mediating the activation of caspase-1 and the cleavage of pro-IL-1β and pro-IL-18 into their active, secreted forms. New data suggest that components of the inflammasome cascade may have roles in influencing inflammasome-independent pathways of cytokine production. These influences on other immune cytokine pathways are complemented by data suggesting that non-inflammasome cytokines can influence the activation of the inflammasome, either directly or by influencing transcription of inflammasome components. The crosstalk between these cytokine cascades may lead to increased abilities for the cell to respond to diverse pathogen threats.

Figure 1. Influence of inflammasome components on the activation of non-Inflammasome cytokines and cytokine signaling pathways

Recent evidence suggests that ASC has an inflammasome-independent role in the activation of MAP kinase and NF-κB signaling, which leads to the transcriptional activation of a panel of cytokines and chemokines. Inflammasome NLRs, including NLRP3 and NLRC5, and the inflammasome viral DNA sensors AIM2 and RIG-I have also been shown to influence the activation of NF-κB and subsequent activation of cytokine transcription. Additional evidence suggests that AIM2 may directly affect the induction of IFN-α by viruses through interaction with the RIG-I/MAVS complex. Recent evidence also suggests that caspase-1 may influence the production of additional cytokines that are processed through the unconventional secretory pathway.

Figure 2. Influence of non-inflammasome cytokines and cytokine signaling pathways on the inflammasome

Many immune pathways downstream of non-inflammasome cytokines influence inflammasome activation, either by transcriptional upregulation of inflammasome components or direct interaction with the inflammasome. While the understanding of the transcriptional control of the NLR sensors is not well understood, it has been demonstrated that NF-κB signaling, Src family kinases, Syk kinase, MAP kinase, and interferon signaling are involved in NLR transcription. Syk kinase and molecules in the interferon and NF-κB signaling cascades can also interact with inflammasome components to influence inflammasome activation.