Abstract
The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.
Highlights
The innate immune system is the first line of host defense and the engagement of germline-encoded pattern-recognition receptors (PRRs) activate it in response to harmful stimuli, such as invading pathogens, dead cells, or environmental irritants [1]
PRRs recognize the presence of unique microbial components, called pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which are generated by endogenous stress, and trigger downstream inflammatory pathways to eliminate microbial infection and repair damaged tissues
A recent study shows that priming signals downstream of TLR4 activate transcriptional factor IRF1 to induce the synthesis of mitochondrial DNA, which is required for NLRP3 inflammasome activation [47]
Summary
The innate immune system is the first line of host defense and the engagement of germline-encoded pattern-recognition receptors (PRRs) activate it in response to harmful stimuli, such as invading pathogens, dead cells, or environmental irritants [1]. BRCC3, BRCA1/BRCA2-containing complex subunit 3; IL-1R, IL-1β receptor; JNK1, JUN N-terminal kinase 1; PKD, protein kinase D; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor In this model, a first signal that is provided by microbial components or endogenous cytokines primes the NLRP3 inflammasome; a second signal from extracellular ATP, pore-forming toxins, or particulate matter activates the NLRP3 inflammasome. A recent study shows that priming signals downstream of TLR4 activate transcriptional factor IRF1 to induce the synthesis of mitochondrial DNA (mtDNA), which is required for NLRP3 inflammasome activation [47]. Multiple molecular and cellular signaling events that are induced by NLRP3 stimuli, including ionic flux, mitochondrial dysfunction and the production of reactive oxygen species (ROS), and lysosomal damage, have been shown to activate the NLRP3 inflammasome (Figure 1)
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