Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors

Yang Yang,Houhui Song,Fushan Shi,Huanan Wang,Mohammed Kouadir

doi:10.1038/s41419-019-1413-8

Yang Yang, Houhui Song + Show 3 more

Open Access

https://doi.org/10.1038/s41419-019-1413-8

Copy DOI

Abstract

The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer’s disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.

Highlights

The innate immunity is the first line of defense that recognizes infection and initiates the process of pathogen clearance and tissue repair
Using G5, a small-molecule inhibitor of deubiquitination, Py et al showed that G5 inhibited NLRP3 inflammasome activation induced by different kinds of activators, including cathepsin, Reactive oxygen species (ROS), or K+ efflux-dependent agonists, but G5 had no effect on AIM2 and NLRC4 inflammasome activation[59]
Understanding the mechanism of NLRP3 inflammasome activation and regulation will be critical for developing treatments of NLRP3 inflammasomerelated inflammatory diseases

Summary

Introduction

The innate immunity is the first line of defense that recognizes infection and initiates the process of pathogen clearance and tissue repair. The priming step (signal 1) is provided by inflammatory stimuli such as TLR4 agonists which induce NF-κB-mediated NLRP3 and pro-IL-1β expression, and the activation step (signal 2) is triggered by PAMPs and DAMPs, thereby promoting NLRP3 inflammasome assembly and caspase-1-mediated IL-1β and IL-18 secretion and pyroptosis[9]. Recent studies have shown that several small molecules, including imiquimod and CL097, can induce ROS production and promote NLRP3 inflammasome activation independent of K+ efflux[22,23].

Results

Conclusion