Inflammasomes: Mechanisms of Action and Involvement in Human Diseases

Abstract

Inflammasome complexes and their integral receptor proteins have essential roles in regulating the innate immune response and inflammation at the post-translational level. Yet despite their protective role, aberrant activation of inflammasome proteins and gain of function mutations in inflammasome component genes seem to contribute to the development and progression of human autoimmune and autoinflammatory diseases. In the past decade, our understanding of inflammasome biology and activation mechanisms has greatly progressed. We therefore provide an up-to-date overview of the various inflammasomes and their known mechanisms of action. In addition, we highlight the involvement of various inflammasomes and their pathogenic mechanisms in common autoinflammatory, autoimmune and neurodegenerative diseases, including atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We conclude by speculating on the future avenues of research needed to better understand the roles of inflammasomes in health and disease.

Keywords: autoimmune; autoinflammatory; inflammasome; interleukin 1; neuroinflammatory and neurogenerative disorders; pyroptosis.

Figure 1

Domain organization of common inflammasome component proteins. NLRP1, NLRP3, NLRP6, NLRP7, NLRP10, NLRP12 and NLRC4 belong to the nucleotide-binding domain and leucine-rich repeat-containing receptor (NLR) protein family, which typically contains a central nucleotide-binding and oligomerization domain (NACHT) domain, an N-terminal Pyrin domain (PYD) domain and a C-terminal leucine-rich repeats (LRR) domain. NLRP1, NLRP10 and NLRC4 deviate from this typical NLR structure. In addition to the common structure, NLRP1 contains a C-terminal function-to-find domain (FIIND) and caspase recruitment domain (CARD), while NLRP10 lacks the LRR domain. The NLRC4 does not have the N-terminal PYD domain but, instead, has an N-terminal CARD domain. AIM2 belongs to the AIM2-like receptor (ALR) protein family and comprises an N-terminal PYD domain and a C-terminal HIN200 domain. Finally, Pyrin consists of an N-terminal PYD domain, a bZIP, B box, coiled-coil and an N-terminal B30.2 domain. Apoptosis-associated speck-like protein containing CARD (ASC) acts as an adaptor protein, consisting of a PYD and CARD, which connects the inflammasome sensor to pro-caspase through PYD and CARD interactions, respectively.

Figure 2

Formation and activation of Pyrin, NLRP1 and AIM2 inflammasomes. (Left) NLRP1 inflammasome formation. Under homeostatic conditions, NLRP1 is inactivated through auto-inhibition or by binding to the inhibitor dipeptidyl peptidases 8 and 9 (DPP8/9). The Kaposi sarcoma-associated herpes virus protein ORF45 is shown to bind to the Linker 1 region, lifting the auto-inhibition and DPP8/9 inhibition of NLRP1 and allowing NLRP1^CT to assemble the inflammasome. Another activation mechanism of the NLRP1 is through proteasomal degradation of the NLRP1^NT. When bacteria or ubiquitin ligases ubiquitinate NLRP1, NLRP1 is directed to the proteasome, where NLRP1^NT is degraded, and NLRP1^CT is released for inflammasome assembly. The DPP8/9 inhibitor Val-boroPro can also direct proteasomal degradation of NLRP1 and subsequent release of NLRP1^CT. (Middle) Pyrin inflammasome activation mechanism. RhoA activity is induced by geranylgeranylation (mevalonate kinase pathway). Pyrin is subsequently phosphorylated by the RhoA effector kinases PKN1 and PKN2, which then bind to the inhibitory protein 14-3-3. When PKN1/2 inhibiting substances are present—i.e., TcdB, C3 toxin, VopS—or when the mevalonate kinase (MVK) pathway is not functioning correctly, PKN1/2 is inactivated and reduced pyrin phosphorylation results in the release of mature IL-1 and IL-18 from the pyrin inflammasome. The creation of the gasdermin D (GSDMD) N-terminal fragment, which forms plasma membrane pores, further promotes the release of IL-1 and IL-18. (Right) AIM2 canonical and non-canonical activation. The canonical activation, which does not involve type I interferon (IFN) activation, is induced when dsDNA is directly recognized by AIM2, triggering the inflammasome formation. On the contrary, the non-canonical activation depends on IFN activity. It is principally involved in bacterial infections that escape the vacuoles, releasing a small amount of DNA that activates cyclic-GMP-AMP synthase and IFI204. Secreted IFN exits the cells and binds to IFN receptors, driving the downstream activation and inducing bacteriolysis which releases large quantities of bacterial DNA recognized by the AIM2 inflammasome. The activated AIM2 inflammasome drives the proteolytic maturation of IL-1β and IL-18 and the maturation of GSDMD, which induces pyroptosis.

Figure 3

Canonical and non-canonical NLRP3 inflammasome activation. Canonical NLRP3 inflammasome activation requires two steps: the priming step and the activation step. In the priming step, TLR stimulation induces the transcription and expression of NLRP3 and pro-IL-1 through NF-κB. Subsequently, various PAMPs and DAMPs induce the activation step by initiating numerous molecular and cellular events, including K+ efflux, mitochondrial dysfunction, reactive oxygen species (ROS) release, and lysosomal disruption. The NLRP3-dependent self-cleavage and activation of pro-caspase-1 self-cleavage and activation leads to the maturation of the pro-inflammatory cytokine’s interleukin 1 (IL-1) and interleukin 18 (IL-18). Additionally, gasdermin D (GSDMD) is cleaved by activated caspase-1, releasing its N-terminal domain, which then integrates into the cell membrane to create pores. These pores allow the release of cellular contents, including IL-1 and IL-18, and trigger pyroptosis, a form of inflammatory cell death. The non-canonical NLRP3 inflammasome is activated by cytosolic LPS, which directly interacts with caspase-4/5 in human (caspase-11 in mice). This interaction results in the autoproteolysis and activation of these caspases. The activated caspases subsequently open the pannexin-1 channel, allowing ATP release from the cell and activating the P2X7R, causing K+ efflux, canonical NLRP3 activation and the maturation of IL-1 and IL-18. In addition, activated caspase-4/5-11 cleaves GSDMD to cause membrane pore formation and pyroptosis, contributing to the release of IL-1 and IL-18.