Trends in Biochemical Sciences
ReviewMechanism and Regulation of NLRP3 Inflammasome Activation
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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