Review
Mechanism and Regulation of NLRP3 Inflammasome Activation

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The NLRP3 inflammasome is an essential mediator of host immune responses through the activation of caspase-1 and interleukin 1 beta (IL-1β)/IL-18.

The NLRP3 inflammasome is thought to sense the disturbance of cellular homeostasis rather than directly recognizing a common motif present in its activators, and multiple cellular signals have been proposed to trigger its activation, including K+ efflux, Ca2+ signaling, mitochondrial dysfunction, and lysosomal rupture.

Noncanonical and alternative inflammasome pathways were recently shown to activate the NLRP3 inflammasome.

Nek7 has emerged as an essential regulator of NLRP3 inflammasome activation.

Members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family and the pyrin and HIN domain (PYHIN) family can form multiprotein complexes termed ‘inflammasomes’. The biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation of interleukin 1 beta (IL-1β) and IL-18 and the induction of pyroptosis, a form of cell death. Unlike other inflammasomes, the NLRP3 inflammasome can be activated by diverse stimuli. The importance of the NLRP3 inflammasome in immunity and human diseases has been well documented, but the mechanism and regulation of its activation remain unclear. In this review we summarize current understanding of the mechanism and regulation of NLRP3 inflammasome activation as well as recent advances in the noncanonical and alternative inflammasome pathways.

Section snippets

The NLRP3 Inflammasome: A Critical Component of Innate Immunity and Contributor to the Pathology of Human Diseases

Inflammasomes are a group of cytosolic protein complexes that are formed to mediate host immune responses to microbial infection and cellular damage [1]. Assembly of an inflammasome triggers proteolytic cleavage of dormant procaspase-1 into active caspase-1, which converts the cytokine precursors pro-IL-1β and pro-IL-18 into mature and biologically active IL-1β and IL-18, respectively 2, 3. Mature IL-1β is a potent proinflammatory mediator in many immune reactions, including the recruitment of

Priming the NLRP3 Inflammasome: Beyond the Induction of NLRP3 and pro-IL-1β

Macrophages, such as mouse bone marrow-derived macrophages, show no or minimal activation of the NLRP3 inflammasome when stimulated with NLRP3 activators, whereas pretreatment with microbial ligands strongly enhances NLRP3 inflammasome activation [16]. This pretreatment is defined as the priming step, which provides the first signal for NLRP3 inflammasome activation. Unlike ASC and caspase-1, the protein amounts of NLRP3 in resting macrophages are thought to be insufficient for NLRP3

Activating the NLRP3 Inflammasome: Integration of Multiple Cellular Signaling Events

Given the chemical and structural diversity of NLRP3-activating stimuli, it is unlikely that NLRP3 physically interacts with its activators. Instead, NLRP3 is likely to sense a common cellular signal induced in response to NLRP3 activators. The identity of this signal is currently under intensive debate. Several molecular and cellular events have been proposed as the trigger for NLRP3 inflammasome activation, including K+ efflux, Ca2+ signaling, reactive oxygen species (ROS), mitochondrial

Noncanonical Inflammasome Pathway

Most Gram-negative bacteria, such as Escherichia coli, Citrobacter rodentium, and Vibrio cholerae, activate a caspase-11-mediated signaling pathway in mouse macrophages resulting in maturation and release of IL-1β/IL-18 and pyroptosis (Figure 2) [59]. The release of IL-1β/IL-18 requires the NLRP3 inflammasome, whereas pyroptosis is independent of it. In contrast to the NLRP3 inflammasome, this pathway is defined as a noncanonical inflammasome pathway because of the requirement for caspase-11

Alternative NLRP3 Inflammasome Pathway

Human monocytes, unlike macrophages, are able to release mature IL-1β in response to TLR ligands alone, such as LPS 29, 72. This may be achieved through microbial activation of the NLRP3 inflammasome through an autocrine mechanism. In this model LPS induces the release of endogenous ATP from human monocytes, which in turn activates the P2X7 receptor to trigger NLRP3 inflammasome activation and IL-1β maturation. Mouse bone marrow-derived dendritic cells can also secrete mature IL-1β in response

Regulators of NLRP3 Inflammasome Activation

Several regulators of NLRP3 inflammasome activation, including double-stranded RNA-dependent protein kinase (PKR), guanylate-binding protein 5 (GBP5), and Nek7 75, 76, 77, 78, 79, have been reported.

PKR regulates the activation of all known inflammasomes, including NLRP1, NLRP3, NLRC4, and AIM2 [76]. Deletion or inhibition of PKR leads to reduced activation of caspase-1 and maturation of IL-1β and IL-18 in response to a wide array of stimuli. However, the role of PKR in inflammasome activation

Concluding Remarks

In the past decade, intense efforts have been put into the investigation of the mechanism of NLRP3 inflammasome activation. However, a unified mechanism has not yet emerged. Recently, progress has been made revealing a critical role for K+ efflux in NLRP3 activation, while the contribution of Ca2+ signaling, ROS, and mitochondrial dysfunction remains controversial. Importantly, the identification of Nek7 as an essential regulator of the NLRP3 inflammasome, as well as the discoveries of a

Acknowledgments

The work on inflammasomes in the Núñez laboratory is funded by NIH grants R01AI063331 and R01DK091191. Y.H. was supported by NIH training grant T32HL007517.

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