Regulation of inflammasome signaling

Abstract

Innate immune responses have the ability to both combat infectious microbes and drive pathological inflammation. Inflammasome complexes are a central component of these processes through their regulation of interleukin 1β (IL-1β), IL-18 and pyroptosis. Inflammasomes recognize microbial products or endogenous molecules released from damaged or dying cells both through direct binding of ligands and indirect mechanisms. The potential of the IL-1 family of cytokines to cause tissue damage and chronic inflammation emphasizes the importance of regulating inflammasomes. Many regulatory mechanisms have been identified that act as checkpoints for attenuating inflammasome signaling at multiple steps. Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance.

Figure 1

Basic mechanisms of activation of the main NLR inflammasomes. NLRP3 is activated by three common cellular events elicited by different stimuli: potassium efflux; the generation of ROS; and phagolysosomal destabilization and the release of endogenous mediators into the cytosol. NLRP1b is activated by anthrax lethal toxin. In the mouse, NLRC4 is activated by NAIP proteins bound to specific ligands. NAIP5 and NAIP6 bind to bacterial flagellin, whereas NAIP2 binds to the bacterial T3SS component PrgJ. These NAIP-ligand complexes subsequently bind and activate NLRC4. LF, lethal factor; PA, protective antigen.

Figure 2

Activation of PYHIN inflammasomes. PYHIN inflammasomes (AIM2 and IFI16) bind directly to their ligand, DNA. The AIM2 inflammasome is activated by cytosolic dsDNA from DNA viruses and cytosolic bacteria; IFI16 is activated by KSHV DNA in the nucleus.

Figure 3

Regulation of inflammasomes by microbial and endogenous products. Many bacterial and viral proteins inhibit inflammasome activation. The poxvirus proteins M013 (myxoma virus) and gp013L (Shope fibroma virus) inhibit transcription of the gene encoding IL-1β and bind ASC to limit inflammasome activation. The poxvirus proteins CrmA, B13R, Serp2 and SPI-2 abolish the proteolytic activity of caspase-1. Other microbial proteins that inhibit inflammasome activation include NS1 (influenza virus), p35 (baculovirus), ExoU, ExoS (P. aeruginosa), YopE and YopT (Y. enterocolitica), Zmp1 (M. tuberculosis), and MviN and RipA (F. tularensis). In contrast, endogenous POPs such as POP1 and POP2 bind to the PYD of ASC and NLRs, respectively, and sequester them from the inflammasome complex. Similarly, endogenous COPs, such as COP1 (pseudo-ICE), INCA, ICEBERG, caspase-12, and Nod2-S, bind to CARD of caspase-1 and sequester it from inflammasome activation.

Figure 4

Regulation of the NLRP3 inflammasome. Type I interferon signaling attenuates NLRP3- and NLRP1-dependent IL-1β responses by two mechanisms (NLRP1 not shown here). IFN-α and IFN-β trigger the production of IL-10, which then acts on the cells in an autocrine and/or paracrine manner to suppress the intracellular concentration of pro-IL-1β. Type I interferon signaling can also inhibit NLRP3- and NLRP1-mediated caspase-1 processing via an unknown mechanism. Autophagy regulates IL-1β production via the removal of damaged mitochondria, which are potent sources of ROS that drive NLRP3 activation. Additionally, autophagosomes sequester intracellular stores of pro-IL-1β and target it for degradation. Effector and memory T cells block NLRP3 and NLRP1 inflammasomes via a cognate mechanism mediated by interactions between ligands of the TNF superfamily and their receptors. Mitophagy, mitochondrial autophagy.

Figure 5

Regulation of the AIM2 inflammasome. Binding of dsDNA by IFI202 (p202) and in some cases by IFI16 can block AIM2 from gaining access to dsDNA. Additionally, LL-37, a human cathelicidin antimicrobial peptide, inhibits activation of the AIM2 inflammasome in psoriasis by forming a complex with self DNA released from the dying cells in the inflammatory milieu.