Mechanisms of NOD-like receptor-associated inflammasome activation

Abstract

A major function of a subfamily of NLR (nucleotide-binding domain, leucine-rich repeat containing, or NOD-like receptor) proteins is in inflammasome activation, which has been implicated in a multitude of disease models and human diseases. This work will highlight key progress in understanding the mechanisms that activate the best-studied NLRs (NLRP3, NLRC4, NAIP, and NLRP1) and in uncovering inflammasome NLRs.

Figure 1. Schematic of the NLRP3 inflammasome activation in response to mitochondria, ER and Ca²⁺ signals

The activation of the NLRP3 inflammasome by its typical stimuli such as ATP, toxin and crystalline reagents involve mitochondria-derived signals such as mROS, mtDNA and cadiolipin. The relocalization of NLRP3 form the cytosol to mitochondria is MAVS-dependent and is pivotal for optimal inflammasome activation. GBP5 promotes NLRP3 signaling to ASC. ER stress has been reported to activate the NLRP3 inflammasome through a mechanism that seems not to require the typical unfolded protein response pathway. Elevated intracellular Ca²⁺ and/or decreased intracellular K⁺ are required for NLRP3 inflammasome activation.

Figure 2. Canonical and non-canonical inflammasome activation pathways

Canonical inflammasomes including NLRP3, AIM2, and NLRC4 activate caspase-1. NLRP3 or AIM2 recruits caspase-1 through the adaptor protein ASC via Pyrin-Pyrin homotypic interactions. The activated caspase-1 results in its proteolytic maturation to the p10 and p20 fragments, and subsequent IL-1β and IL-18 cleavage and secretion. NLRC4 contains a CARD domain and directly binds to the CARD of caspase-1 through homotypic interaction, triggering cytokine (IL-1β and IL-18) maturation and pyroptosis. Non-canonical inflammasome activation leads to caspase-11-dependent pyroptosis. Caspase-11 activation also triggers NLRP3 activation via an unknown mechanism (not shown).