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Activation and Pharmacological Regulation of Inflammasomes - PubMed

  • ️Sat Jan 01 2022

Review

Activation and Pharmacological Regulation of Inflammasomes

Chen Chen et al. Biomolecules. 2022.

Abstract

Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered.

Keywords: AIM2; GSDMD; IL-1β; NLRP3; caspase; disease; inflammasome; inflammation; inhibitor; targeting.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Domain architecture of canonical inflammasome sensors. Overview and alignment of the distinct domains for sensors that initiate canonical inflammasome signaling.

Figure 2
Figure 2

Assembly of canonical inflammasomes. An organization summary for the assembly of canonical inflammasomes, comprising sensors, adaptors/ASC, and effectors/caspase-1.

Figure 3
Figure 3

Activation of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome undergoes two sequential steps. The priming process (signal 1) includes the recognition of PAMPs/DAMPs through TLRs and/or sensing of TNFα through TNFR, which induces the expression of NLRP3, pro-IL-1β, and pro-IL-18 proteins via NF-κB signaling. The activation process requires a signal (signal 2) that multiple pathogenic and sterile inflammatory cues can provide. Oligomerization and activation of NLRP3 inflammasome lead to the processing of pro-caspase-1 into the mature form, which in turn processes pro-IL-1β, pro-IL-18, and GSDMD. The released N-terminal domain of GSDMD enters the membrane, forming a pore structure for releasing matured IL-1β and IL-18 into the extracellular space, inducing pyroptosis and causing inflammation.

Figure 4
Figure 4

Inflammasome-related human diseases. Canonical inflammasomes are involved in multiple inherited diseases (yellow-shaded boxes) and non-hereditary sterile inflammatory diseases (blue-shaded boxes). The highly relevant inflammasomes responsible for sterile inflammatory diseases are labeled in red.

Figure 5
Figure 5

Pharmacological targeting of the NLRP3 inflammasome mechanisms. A wide variety of small synthetic molecules, natural compounds, and antibodies have been developed to target the canonical NLRP3 inflammasome signaling components as research tools and medicines in trials and clinics. Natural, but not synthetic, products are labeled in purple.

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This work was supported by the National Key Research and Development Program of China (2021YFA1301401 to P.X.) and the NSFC Projects (31725017 and 31830052 to P.X.).

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