Inflammasomes: molecular regulation and implications for metabolic and cognitive diseases

Abstract

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multi-protein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-κB-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 (P2X7R), which results in K(+) efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and/or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

Fig. 1.

The NLRP3 inflammasome regulates the caspase-1 dependent maturation and secretion of pro-inflammatory cytokines. Activation of the NLRP3 inflammasome typically requires a bimodal signaling pathway. A Toll-like receptor (TLR)-dependent priming step activates the NF-κB-dependent transcription of NLRP3 and the pro-forms of the pro-inflammatory cytokines (i.e., IL-1β and IL-18). A second signal involves the activation of the P2X₇R receptor by stimulation with exogenous ATP, which triggers potassium ion (K⁺) efflux. Oligomerization of NLRP3 is followed by recruitment of the adaptor molecule ASC and the pro-form of caspase-1, leading to the activation (cleavage) of caspase-1. Activated caspase-1 in turn catalyzes the cleavage of IL-1β and IL-18. The NLRP3 inflammsome may be activated by agents that cause mitochondrial dysfunction, leading to the generation of mitochondrial reactive oxygen species (ROS). Furthermore, the NLRP3 inflammasome may be activated by particulates such as monosodium urate or silica, in a mechanism that may involve disruption of the lysosomes.

Fig. 2.

NLRP3 has been implicated in pro-pathogenic responses related to several human diseases, including neurocognitive disorders and metabolic disorders, although the mechanisms remain incompletely clear. Neurons and astrocytes may represent targets of NLRP3-dependent inflammatory processes, leading to the promotion of neurocognitive disorders. Adipocyte differentiation and growth have been linked to NLRP3-dependent processes in obesity. Hepatic insulin resistance and inflammation may also be mediated in part by NLRP3-dependent inflammation.