Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies

Abstract

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases. In this review, we summarize the main features of the predominant types of inflammasomes involved in gastrointestinal immune responses and their implications in intestinal disease, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), celiac disease, and Colorectal Cancer (CRC). In addition, we report therapeutic discoveries that target the inflammasome pathway, highlighting promising novel therapeutic strategies in the treatment of intestinal diseases. Collectively, our understanding of the mechanisms of intestinal inflammasome activation and their interactions with other immune pathways appear to be not fully elucidated. Moreover, the clinical relevance of the efficacy of inflammasome inhibitors has not been evaluated. Despite these limitations, a greater understanding of the effectiveness, specificity, and reliability of pharmacological and natural inhibitors that target inflammasome components could be an opportunity to develop new therapeutic options for the treatment of intestinal disease.

Keywords: colorectal cancer; gastrointestinal disease; inflammasome; inflammatory bowel disease; miRNAs.

Figure 1

Domain structures of inflammasome components. NLR sensors contain a common central domain composed of a nucleotide-binding domain (NBD) and leucine-rich-repeat domain (LRR), but differ in regards to the N-Terminal domain required for Caspase-1 recruitment, consisting of the PYRIN domain (PYD) and caspase activation and recruitment domain (CARD). Moreover, the NLRP1 sensors differ in regard to the function-to-find domain (FIIND) and the CARD domain in the C-terminal. AIM2-like receptor sensors are composed of the N-Terminal PYD and C-Terminal IFN-inducible nuclear protein with 200-amino acids (HIN-200). Pyrin/TRIM20 sensors are composed of the N-Terminal PYD; a central region consists of an α-helical coiled-coil domain (C-C) and a zing finger domain (B-Box), as well as a C-terminal B30.2/SPRY domain. The adapter protein ASC is composed of a CARD and a PYD, whereas the effector protein pro-caspase-1 consists of a CARD domain and a catalytic domain. Created in BioRender.com.

Figure 2

NLRP1 inflammasome activation. In the presence of bacterial and parasites infections, ATP depletion, and UV radiation, NLRP1 undergoes FIIND cleavage. The N-terminal domain is ubiquitinated and degraded by proteasomes, whereas the resulting FIIND-CARD fragment recruits the adapter protein ASC, which brings in pro-caspase-1, leading to the inflammasome complex. After proteolytic cleavage, the active caspase-1 results in IL-1β and IL-18 activation and the induction of pyroptosis. Created in BioRender.com.

Figure 3

NLRP3/6 inflammasome activation. The activation of the NLRP3/6 inflammasome involves a two-step process. The first step, called “priming signal”, consists of the recognition of PAMPs or DAMPs, which results in NF-κB activation and the overexpression of inflammasome components. The second step, called “activation signal”, is provided by RNA viruses, extracellular ATP, the K⁺ efflux, or pore-forming toxins that lead the inflammasome assembly and oligomerization. NEK7 is a regulator that interacts with NLRP3 and mediates inflammasome assembly. The inflammasome complex activates caspase-1, which activates IL-1β and IL-18 and induces pyroptosis. The activation of the NLRP3 sensor can be regulated by post-transcriptional mechanisms and, in the absence of inflammatory stimuli, can be degraded by proteasomes. Created in BioRender.com.

Figure 4

NLRC4 inflammasome activation. The presence of specific bacterial protein ligands is recognized by the NLR family of apoptosis-inhibitory proteins (NAIP). The NAIP-ligand complex recruits NLRC4, which therefore binds pro-caspase-1 and induces inflammasome oligomerization. As a result, the active caspase-1 induces IL-1β and IL-18 activation and release, as well as pyroptosis. Created in BioRender.com.

Figure 5

Inflammasomes inhibitors. Graphical representation of the inflammasome pathways and inhibitors with related targets. Black font corresponds to pharmacological compounds, green font corresponds to natural compounds, and purple font corresponds to miRNAs. Created in BioRender.com.