Inflammasome activation: from molecular mechanisms to autoinflammation

Abstract

Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro-inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL-1β and IL-18 pro-inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post-translational modifications, ubiquitination and phosphorylation, as well as single-domain proteins that competitively bind to key inflammasome components, such as the CARD-only proteins (COPs) and PYD-only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro-inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti-inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small-molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.

Keywords: NLRC4; NLRP3; Pyrin; autoinflammatory disorders; inflammasome; inflammation.

Figure 1

Domain structure of inflammasomes and regulators. Different types of inflammasomes are shown; Nucleotide‐binding and oligomerisation domain NOD‐like receptors (NLRs): NLRP1, NLRP3, NLRP6, NLRC4 and NLRC5 all contain a central NACHT domain and a and C‐terminal leucine‐rich repeats (LRRs) domain; NLRP1, NLRP3, NLRP6 encompass an N‐terminal Pyrin domain (PYD); NLRP1, NLRC4 and NLRC5 contain a caspase recruitment domain (CARD); only the human NLRP1 contains a function‐to‐find domain (FIIND). Pyrin inflammasome consists of a PYD, a B‐box (BB), a coiled‐coil (CC), and a B30.2 domain. The AIM2‐Like Receptors (ALR) AIM2 and IFI16 are members of PYHIN family, containing an N‐terminal PYD and C‐terminal HIN‐200 domain. PYD‐only proteins (POPs) and CARD‐only proteins (COPs) are composed of PYD or CARD domains, accordingly, with different amino acid (AA) composition. The adaptor protein ASC links inflammasome sensors and caspase‐1 via the PYD and CARD domains.

Figure 2

NLRP3 inflammasome activation. Danger‐associated molecular patterns (DAMPs) or pathogen‐associated molecular patterns (PAMPs) are able to induce the priming step inducing the transcriptional upregulation of inflammasome components. DAMPs or PAMPs are subsequently sensed inducing oligomerisation of the inflammasome sensor, NLRP3. Caspase‐1, NEK7, ASC and the NLRP3 all together form the NLRP3 inflammasome. The NLRP11bound to ASC is required for NLRP3 oligomerisation and ASC polymerisation. The inflammasome is activated and active caspase‐1 cleaves pro‐IL‐1β and pro‐IL‐18 to their mature forms IL‐1β and IL‐18 which get secreted through gasdermin D pores (GSDMD); alternatively, IL‐1β and IL‐18 can be secreted via different mechanism avoiding GSDMD.

Figure 3

Inflammasome sensors, activators and related disorders. The NLRP1, NLRP3, pyrin, NLRC4 and AIM2/IFI16 with their current ligands and intracellular mediators involved in activation of these molecules. NLRP1 detects lethal toxin Bacillus anthracis (B. anthracis), Shigella flexneri (S. flexneri), Listeria monocytogenes (L. monocytogenes). NLRP3 is an overall sensor for several PAMPs and DAMPs (Figure 2) responding to intracellular damage induced by pathogenic or sterile insults. Pyrin inflammasome is activated by bacterial toxins that modify RhoA GTPases. The NLRC4 inflammasome detects bacterial proteins via NLR family‐apoptosis inhibitory proteins (NAIPs) and can assemble an inflammasome with or without ASC. Absent in melanoma 2 (AIM2) and IFNγinducible protein‐16 (IFI16) detect dsDNA via their HIN‐200 domains. When these sensors are chronically activated or not properly regulated, inflammatory‐related conditions are caused by these inflammasomes. MSPC, Multiple self‐healing palmoplantar carcinoma; FKLC, Familial keratosis lichenoides chronica; NAIAD, NLRP1‐associated autoinflammation with arthritis and dyskeratosis; MWS, Muckle–Wells syndrome; FCAS, familial cold autoinflammatory syndrome; MDS, myelodysplastic syndromes; neonatal‐onset multisystem inflammatory disease (NOMID)/chronic infantile neurological nutaneous and articular (CINCA); PAAND, pyrin associated autoinflammation with neutrophilic dermatosis; FMF, familial mediterranean fever; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne; MKD, mevalonate kinase deficiency; AIFEC, autoinflammation and infantile enterocolitis; NLRC4‐MAS, NLRC4 macrophage activation syndrome; CKD, chronic kidney disease.