Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases

Abstract

Inflammasomes are cytosolic pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from invading pathogens and damaged tissues, respectively. Upon activation, the inflammasome forms a complex containing a receptor protein, an adaptor, and an effector to induce the autocleavage and activation of procaspase-1 ultimately culminating in the maturation and secretion of IL-1β and IL-18 and pyroptosis. Inflammasome activation plays an important role in host immune responses to pathogen infections and tissue repair in response to cellular damage. The NLRP3 inflammasome is a well-characterized pattern recognition receptor and is well known for its critical role in the regulation of immunity and the development and progression of various inflammatory diseases. In this review, we summarize recent efforts to develop therapeutic applications targeting the NLRP3 inflammasome to cure and prevent chronic inflammatory diseases. This review extensively discusses NLRP3 inflammasome-related diseases and current development of small molecule inhibitors providing beneficial information on the design of therapeutic strategies for NLRP3 inflammasome-related diseases. Additionally, small molecule inhibitors are classified depending on direct or indirect targeting mechanism to describe the current status of the development of pharmacological inhibitors.

Inflammasomes in Alveolar Bone Loss

“…TLR-, NOD ligand-, or inflammatory cytokine-mediated NF-κB-dependent transcriptional signaling provides the first signal for NLRP3 priming, leading to an increase in transcriptional and translational expression of NLRP3 inflammasome components and subsequent post-translational modifications, such as phosphorylation and ubiquitination ( 40 ). Once primed, the NLRP3 inflammasome can be activated by a plethora of stimuli and agonists, including (but not limited to) infection by bacteria, viruses, and fungi, crystalline or particulate matter, reactive oxygen species (ROS) generated by ATP signaling via the P2X7 receptor, calcium influx, potassium efflux, chloride efflux, mitochondrial damage, oxidized mitochondrial DNA, and lysosomal destabilization, as reviewed elsewhere ( 41 ). These different agonists may converge into similar downstream events that increase cell stress as the second signal, leading to the assembly and eventual activation of NLRP3, which requires the interaction of its LRR and NBD with NIMA-related kinase 7 (NEK7) ( 31 ).…”

Self-Control of Inflammation during Tail Regeneration of Lizards

“…PRRs recognize microbial components, known as pathogen-associated molecular patterns (PAMPs), to activate specific signaling pathways and lead to distinct anti-pathogen responses [ 55 ]. Furthermore, they can interact with the damage-associated molecular patterns (DAMPs) to initiate cellular inflammatory responses [ 56 ]. PRRs include Toll-like receptors (TLRs), Nod-like receptor, and C-type lectin receptor families, among which TLRs have the maximum number of transcripts in lizard splenic transcriptome [ 57 ].…”

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

“…Among the recognized triggers, we can mention mitochondrial DNA and ROS, ion flux (K + , Cl − , Ca 2+ ), free fatty acids (FAs), and others [ 56 ]. While inflammasome description is far beyond the topic of this review, we wish to redirect interested readers to some more focused recent reviews [ 57 , 58 ].…”