The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

Abstract

Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1β activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

Figures

Figure 1

NLRs and inflammasomes. (a) Schematic representation of human NLR structures. NLR family comprises the three main subfamilies NLRP, NOD and IPAF/NAIP, characterized by the conserved central oligomerization NACHT domain and the C-terminal LRR domain. The N-terminal CARD or PYD are present in the NOD and NLRP subfamilies, respectively. (b) Among the NLRs, NLRP1, NLRP3 and IPAF participate in the formation of the inflammasome platform. AIM2, not belonging to the NLR family, has also been identified as forming part of a specific inflammasome. AIM2, absent in melanoma 2; CARD, caspase recruitment domain; IPAF, ICE-protease-activating factor; LRR, leucine-rich repeat; NAIP, neuronal apoptosis inhibitory protein; NLR, nucleotide-binding oligomerization domain-containing protein-like receptor; NOD, nucleotide-binding oligomerization domain; PYD, pyrin domain.

Figure 2

NLRP3 inflammasome activation pathways. The assembly of the NLRP3 inflammasome in innate cells is induced by several different stimuli, including MAMPs (pink box) or sterile DAMPs (light blue box). A first priming signal delivered predominantly by MAMPs, such as LPS, is required to promote IL-1β transcription via NF-κB translocation to the nucleus. Inflammasome oligomerization and activation can be induced by bacterial and fungal moieties, pore forming toxins, or viral dsDNA and RNA. Upon binding to the P2X7 receptor, ATP also triggers inflammasome formation through K+ efflux and opening of the pannexin-1 channel. Particulates, such as MSU, fibrillar amyloid β, CPPD, silica, asbestos and alum, are phagocytosed and activate the inflammasome. MSU can also promote inflammasome formation via frustrated phagocytosis. ROS formation induced by certain inflammasome activators also mediates inflammasome assembly via recruitment of TXNIP. Inflammasome oligomerization results in ASC-mediated caspase-1 activation responsible for cleavage and release of IL-1β and IL-18 cytokines. ASC, apoptotic-associated speck like protein containing a caspase recruitment domain; CPPD, calcium pyrophosphate dihydrate; DAMP, danger-associated molecular pattern; LPS, lipopolysaccharide; MDP, muramyl dipeptide; MAMP, microbial-associated molecular pattern; MSU, monosodium urate; ROS, reactive oxygen species; TXNIP, thioredoxin-interacting protein; Casp-1, caspase-1.

Figure 3

Mutations and polymorphisms in the NLRP3 gene are associated with diseases. Schematic representation of residue substitutions in NLRP3 protein (upper panel), or polymorphysms in NLRP3 gene intronic regions (lower panel). Single residue-allelic variants associated with cryopyrin-associated periodic syndromes or with other NLRP3-related diseases are highlighted in blue and pink, respectively. LRR, leucine-rich repeat; NAD, NACHT-associated domain; PYD, pyrin domain.

Figure 4

Proposed ranking of human diseases based on penetrance and frequency of inflammasome polymorphisms. Missense point mutations in genes encoding inflammasome components exhibit high penetrance and contribute to the pathogenic autoinflammation, leading to severe but rare autoinflammatory syndromes, such as CAPS. Allelic variants of inflammasome encoding genes in combination with other genetic polymorphisms affecting immune cells lead to more common autoinflammatory-like syndromes, including Crohn's diseases, RA and JIA. Multifactorial disorders highly diffused in the human population, such as infections, autoimmunity, cancer, cardiovascular and neurological diseases, might be associated with polymorphisms in inflammasome-encoding genes of low and variable penetrance. CAPS, cryopyrin-associated periodic syndrome; JIA, juvenile idiopathic arthritis; RA, rheumatoid arthritis.