Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis

Abstract

Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut-brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.

Fig. 1. Inflammasome complexes.

The inflammasome sensors NLRP1b, NLRP3, NLRC4, AIM2 and pyrin are all capable of forming a canonical inflammasome complex containing the adaptor protein ASC and the cysteine protease caspase 1. NLRP1b and NLRC4 also recruit caspase 1 without ASC owing to the presence of a CARD domain in their structure^–. Activation of NLRP3 and NLRC4 requires the kinase NEK7 and the NLR family members neuronal apoptosis inhibitory proteins (NAIPs), respectively. Caspase 1 cleaves the precursor cytokines pro-IL-1β and pro-IL-18 and the pore-forming protein gasdermin D. The active fragment of gasdermin D oligomerizes and forms pores on the cell membrane, resulting in pyroptosis^–. These pores also allow passive release of biologically active IL-1β and IL-18 from the cell. The non-canonical inflammasome is defined by a requirement for human caspase 4, human caspase 5 or mouse caspase 11 for the activation of the NLRP3 inflammasome complex. Activation of these caspases leads to cleavage of gasdermin D and pyroptosis^–. The pore-forming fragment of gasdermin D activates the NLRP3 inflammasome and caspase 1-dependent maturation of IL-1β and IL-18 (refs^,).

Fig. 2. Expression of inflammasome sensors and related molecules by cell type.

a | Expression in humans. b | Expression in mice. References for expression data are given in Supplementary table 1. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD); NAIP, neuronal apoptosis inhibitory protein; NLRC, nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein; NLRP, NACHT, LRR and PYD domains-containing protein.

Fig. 3. Inflammasomes recognize gastrointestinal bacteria, viruses, protozoa and helminths.

Pathogens carry a plethora of pathogen-associated molecular patterns (PAMPs). These PAMPs either directly bind and activate an inflammasome sensor or induce a physiological change in the cell that is sensed by an inflammasome sensor. Pathogens also cause substantial damage to the host cell, a process that induces the liberation of danger-associated molecular patterns (DAMPs) that activate the inflammasome. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD); LPS, lipopolysaccharide; NAIP, neuronal apoptosis inhibitory protein; NLRC4, nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4; NLRP3, NACHT, LRR and PYD domains-containing protein 3; ROS, reactive oxygen species; T3SS, type 3 secretion system.

Fig. 4. Inflammasomes and related molecules contribute to the killing and clearance of gastrointestinal pathogens in intestinal cells and immune cells.

a | Inflammasomes mediate host protection against Gram-negative bacteria by inducing the secretion of IL-1β and IL-18 and pyroptosis^,,,,,,,. NLRP6 and NLRP12 negatively regulate inflammation^,,,. NLRP6 responds to Toll-like receptor (TLR)-induced autophagy in goblet cells and mediates secretion of mucus. RNA-bound DEAH box protein 9 (DHX9) interacts with NLRP9b, inducing the assembly of an inflammasome complex. The NLRP6–DHX15 complex binds to viral RNA and induces the production of type I and type III interferons. b | Intestinal macrophages can discriminate pathogens from commensals. c | Activation of caspase 1, caspase 8 or caspase 11 leads to cell death, which removes and extrudes the infected enterocyte from the epithelium^,,. d | The inflammasome can reduce bacterial load by inhibiting bacterial uptake, which limits macrophage movement and stiffness, and can promote the production of reactive oxygen species (ROS). Pyroptotic macrophages liberate either whole bacteria or bacteria entrapped within pore-induced intracellular traps. These entities are phagocytosed by neutrophils^,. ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD); dsRNA, double-stranded RNA; EMCV, encephalomyocarditis virus; KC, keratinocyte chemoattractant (also known as CXCL1); MAVS, mitochondrial antiviral-signalling protein; NAIP, neuronal apoptosis inhibitory protein; NF-κB, nuclear factor-κB; NLRC4, nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4; ssRNA, single-stranded RNA.

Fig. 5. Development of intestinal inflammation and cancer is regulated by the inflammasome–microbiota axis.

a | Oncogenic assaults such as azoxymethane (AOM) and dextran sodium sulfate (DSS) cause damage, leading to the release of danger-associated molecular patterns (DAMPs). Bacteria can invade enterocytes and introduce pathogen-associated molecular patterns (PAMPs) into the host cell. DAMPs and PAMPs are sensed by inflammasomes^–,,,. IL-18 promotes downregulation of soluble IL-22-binding protein (IL-22BP), which controls the ability of IL-22 to suppress inflammation or induce tumorigenesis in the gut. b | Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4 (NLRC4) and neuronal apoptosis inhibitory proteins (NAIPs) can block cellular proliferation and tumorigenesis^,. c | DNA-dependent protein kinase (DNA-PK) induces colorectal tumorigenesis via activation of AKT and the transcription factor MYC^,. This response is inhibited by absent in melanoma 2 (AIM2^),. AIM2 also triggers the production of antimicrobial peptides (AMPs) in intestinal epithelial cells to modulate the gut microbiota^,. A similar negative regulatory role for NLRC3 has been described. d | NLRP6 and NLRP12 contribute to the pathogenesis of gastrointestinal infection, acute colitis and colorectal cancer^,,,–,,,,. Question marks denote unknown mediators. GFR, growth factor receptor; mTOR, mechanistic target of rapamycin; NLRP, NACHT, LRR and PYD domains-containing protein; PI3Ks, phosphoinositide 3-kinases; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; T3SS, type 3 secretion system; TLR, Toll-like receptor.