How location and cellular signaling combine to activate the NLRP3 inflammasome

Abstract

NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by infection and sterile inflammation. Upon detection of an activating stimulus, NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome, which promotes the helical oligomeric assembly of the adaptor molecule ASC. ASC oligomers provide a platform for caspase-1 activation, leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D, which can induce a lytic form of cell death. Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation. This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles. We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

“…Depending on the host species, NLRP1 is conformationally activated by pathogen‐derived factors that either mediate ubiquitination and limited proteosomal degradation of the NLRP1 N‐terminal domain or direct cleavage of the N‐terminus; these modifications liberate the NLRP1 C‐terminal domain to recruit ASC 70 . The NLRP3 initiator acts as a sensor of perturbed cellular homeostatic parameters that include: (i) rapid decreases in cytosolic [K + ] triggered by activated host cell ion channels or microbial pore‐forming exotoxins; (ii) disruption of mitochondrial or lysosomal integrity; and (iii) disorganization of the complex inter‐membrane network between endosomes, the trans‐Golgi apparatus and the endoplasmic reticulum 71,72 . Pyrin (encoded by the MEFV/Familial Mediterranean Fever gene in humans) detects inhibition of RhoA GTPases by bacterial ADP‐ribosyl transferase toxins with the resulting covalent modification disrupting the homeostatic interaction of RhoA with its downstream PKR‐family kinase effectors.…”

“…First, upon activation, canonical ASC‐containing inflammasomes progressively assemble into the large macromolecular complexes morphologically identified as the so‐called “ASC specks.” In macrophages and other mononuclear cells, ASC‐containing inflammasomes typically coalesce into a single centrally located ASC speck adjacent to the nucleus 4,72 . Although few studies have directly imaged ASC specks in neutrophils, Karmakar et al 51 reported that neutrophils accumulate multiple and smaller ASC specks in response to NLRP3 inflammasome activation by pneumolysin.…”

“…In macrophages and other mononuclear cells, ASC-containing inflammasomes typically coalesce into a single centrally located ASC speck adjacent to the nucleus. 4,72 Although few studies have directly imaged ASC specks in neutrophils, Karmakar et al 51 reported that neutrophils accumulate multiple and smaller ASC specks in response to NLRP3 inflammasome activation by pneumolysin. This likely reflects effects of polymorphonuclear architecture to favor formation of multiple specks adjacent to individual lobes of the atypical nucleus.…”

Inflammatory cell death: how macrophages sense neighbouring cell infection and damage

“…Briefly, inflammasome signalling is a two-step process. During the first step, PRRs recognise PAMPs or DAMPs and activate NFκB signalling, increasing pro-IL-1β expression and priming the inflammasome sensors for activation [ 66 ]. A second signal, such as an IAV infection, triggers oligomerisation of the inflammasome sensor scaffold.…”

The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

“…The nod-like receptor protein 3 (NLRP3) inflammasome is the most widely studied of the inflammasomes. It is composed of a sensor (NLRP3), an adapter (apoptosis-associated spotted protein, ASC), and an effector (cysteine aspartate protease 1, caspase-1) [ 11 , 12 ]. The level of NLRP3 expression under steady-state conditions is insufficient for the activation of the NLRP3 inflammasome [ 13 ].…”