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Abstract
Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation.
Highlights
Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns
Direct activation of NLRP3 by K+ efflux The stimulatory effect that cytosolic K+ depletion has on IL-1β proteolytic processing and secretion from LPS-primed macrophages and monocytes, in response to compounds such as ATP or nigericin, was observed long before the discovery of inflammasomes[1,2,3]
The dramatic decrease in [K+]i required for NLRP3 activation, estimated as a drop of at least ~20–30%5, can be expected to be accompanied by either a counter-flux of cations or a “co-flux” of anions, which should be provided by NLRP3 stimuli
Summary
A number of molecular players involved in NLRP3 activation have been identified. Major progress has been made in our understanding of how intracellular LPS triggers caspase-11, leading to proteolytic processing of pannexin-1 and gasdermin D, and to non-canonical NLRP3 inflammasome activation. The mechanism by which human monocytes activate NLRP3 in response to extracellular LPS as a single stimulus has been solved and shown to rely on TLR4/TRIF-mediated activation of the RIPK1FADD-caspase-8 cascade. Physiologically relevant mechanisms, such as autophagy and cAMP signaling, have been proposed to down-regulate the activation of NLRP3, demonstrating the physiological importance of limiting NLRP3 inflammasome responses. The discovery of the dual function of gasdermin D (as a downstream effector of caspase-11 required for non-canonical NLRP3 activation and a substrate of inflammatory caspases required for pyroptosis) calls for closer investigation of the mechanism of action of this protein. Grant information The author(s) declared that no grants were involved in supporting this work
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