Inflammasomes: current understanding and open questions

Abstract

The innate immune system relies on its capability to detect invading microbes, tissue damage, or stress via evolutionarily conserved receptors. The nucleotide-binding domain leucine-rich repeat (NLR)-containing family of pattern recognition receptors includes several proteins that drive inflammation in response to a wide variety of molecular patterns. In particular, the NLRs that participate in the formation of a molecular scaffold termed the "inflammasome" have been intensively studied in past years. Inflammasome activation by multiple types of tissue damage or by pathogen-associated signatures results in the autocatalytic cleavage of caspase-1 and ultimately leads to the processing and thus secretion of pro-inflammatory cytokines, most importantly interleukin (IL)-1β and IL-18. Here, we review the current knowledge of mechanisms leading to the activation of inflammasomes. In particular, we focus on the controversial molecular mechanisms that regulate NLRP3 signaling and highlight recent advancements in DNA sensing by the inflammasome receptor AIM2.

Fig. 1

Members of the human NLR family. The known human NLR proteins are depicted and grouped according to their N-terminal domains. Grouping NLRs according to their N-terminal domain, five distinct families can be identified: NLRA [A stands for AD (acidic activation domain)], NLRB [B stands for BIR (baculovirus inhibitor of apoptosis) domain], NLRC [C stands for CARD (caspase recruitment domain)], NLRP (P stands for pyrin domain), and NLRX (X stands for domain with no strong homology to the N-terminal domain of any other NLR subfamily member)

Fig. 2

Known inflammasomes. The four known inflammasomes are depicted. NLRP1, NLRP3, and AIM2 all indirectly recruit and thereby activate caspase-1 through the bridging molecule ASC. IPAF has been shown to activate caspase-1 independent of ASC, yet there are several reports that stress the requirement for ASC in this process. Apart from this controversy, the exact role of NOD2 and caspase-5 in the NLRP1 inflammasome has to be elucidated and the interaction of NAIP5 with NLRC4 also needs additional clarification

Fig. 3

The NLRP3 inflammasome. NLRP3 expression is the limiting factor in cells that can principally respond to NLRP3 activation. Stimulation of PRRs or cytokine receptors leads to the upregulation of NLRP3 expression and also induces pro-IL-1β expression (priming step). The activation of NLRP3 itself is distinct from this initial priming step. Three presumably distinct pathways have been postulated that can lead to the activation of NLRP3 (activation step). Efflux of potassium, which is initiated by pore-forming toxins, membrane disruption, or ligand-triggered channels, leads to NLRP3 inflammasome assembly by a yet-unknown mechanism. On the other hand, it has been shown that lysosomal disintegration, which leads to the leakage of lysosomal enzymes into the cytosol, can also trigger NLRP3 activation. The lysosomal protease cathepsin B plays a major role in this pathway, yet the direct link between cathepsins and NLRP3 activation hasn’t been elucidated. Lastly, it has been demonstrated that production of reactive oxygen species (ROS), which can be triggered by numerous means, leads to the indirect activation of NLRP3 through the release of TXNIP from thioredoxin. TXNIP can then bind to NLRP3

Fig. 4

The AIM2 inflammasome. AIM2 directly binds to its ligand, which is double-stranded DNA. Following ligand binding, AIM2 recruits ASC and thereby leads to caspase-1 activation. Various exogenous triggers of the AIM2 inflammasome have been identified: vaccinia virus (depicted), mouse cytomegalovirus, L. monocytogenes, and F. tularensis. At the same time, it is tempting to speculate whether DNA of endogenous origin can also lead to AIM2 activation. This could, for example, include DNA antibody complexes found in autoimmune disease or DNA released from phagocytosed apoptotic cells