The NLRP3 inflammasome: contributions to inflammation-related diseases

Abstract

The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β and IL-18. Multiple studies have demonstrated the importance of the NLRP3 inflammasome in the development of immune and inflammation-related diseases, including arthritis, Alzheimer’s disease, inflammatory bowel disease, and other autoimmune and autoinflammatory diseases. This review first explains the activation and regulatory mechanism of the NLRP3 inflammasome. Secondly, we focus on the role of the NLRP3 inflammasome in various inflammation-related diseases. Finally, we look forward to new methods for targeting the NLRP3 inflammasome to treat inflammation-related diseases, and provide new ideas for clinical treatment.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition

“…67 Moreover, compound 3-37 was optimized from the weak potent triazolopyrimidone 3-36, which resulted in an improved IC 50 value of 13 nM in PBMC. This highlights the potential of the [1,2,4]triazolo[1,5a]pyrimidine-7(4H)-thione group as a core pharmacophore. 68 Compounds 3-38 to 3-42 all featured formate esters.…”

“…The introduction of small substituents, such as isopropyl (5-S7-13) or cyclopropyl (5-S7-14) at the R 3 position were beneficial for the activity. Compounds 5-S7-14 and 5-S7-15 featuring [1,2,4]triazolo [4,3-a]pyridine as the R 1 group demonstrated the highest activity within this scaffold with the same IC 50 values of 23 nM.…”

“…The bicyclic inhibitors were modified or simplified to reduce the complexity of the thienopyrrolotriazinacetamide moiety (Figure 12A,B). Like Scaffold 5 (S5), the pyrrolidine [1,2d] [1,2,4]triazine-2-alkyl acetamides were identified by the removal of the thiophene ring. 103 R 1 and R 2 on Scaffold 5 resembled the Scaffold 1 mentioned in Figure 10, while R 3 could be hydrogen; halogen; substituted alkyl, alkenyl, alkoxy, a nitrogen-substituted group, (hetero)aryl group, and fat (hetero)ring.…”

“…Under normal circumstances, NLRP3 inflammasome activation is carefully regulated to protect against pathogenic threats and prevent host damage . However, dysregulation of the NLRP3 inflammasome has been implicated in the pathogenesis of several diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), gout, cryopyrin-associated periodic syndrome (CAPS), and many other diseases. , The pathology of AD is characterized by the accumulation of amyloid-beta (Aβ) in plaques, the presence of hyperphosphorylated tau in neurofibrillary tangles (NFT), and neuroinflammation. The loss of NLRP3 inflammasome has been shown to ameliorate cognitive deficits in mice by reducing tau protein hyperphosphorylation and aggregation through the regulation of phosphatase and tau protein kinase .…”

Influence of metallic particles and TNF on the transcriptional regulation of NLRP3 inflammasome-associated genes in human osteoblasts

“…The inflammasome activators do not interact directly with NLRP3 but instead induce a common cellular signal, which can be detected by NLRP3 ( 6 ). Various molecular and cellular stimuli, such as ion flux, mitochondrial dysfunction, production of reactive oxygen species (ROS) or lysosomal damage, as well as silica particles, asbestos crystals, and urate, ultimately activate the NLRP3 inflammasome ( 3 , 5 , 11 – 15 ). The NLRP3 inflammasome mediates the activation of caspase-1 (CASP1), IL-1β, and IL-18 to induce inflammation.…”