Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

Abstract

Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β’s actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.

Protective effects of baicalin magnesium on non-alcoholic steatohepatitis rats are based on inhibiting NLRP3/Caspase-1/IL-1β signaling pathway

“…[ 35 ], which in turn further activates NLRP3. The activated NLRP3 recruits to pro-caspase-1, leading to the activation of caspase-1 [ 36 ], then the activated caspase-1 processes pro-IL-1 β and pro-IL-18 for cleavage and processing, forming mature IL-1 β and IL-18 and releasing them extracellularly [ 37 , 38 ], exacerbating the inflammatory response [ 39 – 42 ], thus promoting the development and progression of NASH. TNF- α is capable of participating in systemic inflammatory responses and can transmit information to the nucleus through specific receptors on cell membranes, resulting in complex biological activities.…”

Investigating the Anti-Inflammatory Effects of RCI001 for Treating Ocular Surface Diseases: Insight Into the Mechanism of Action

“…Based on our previous and present findings, RCI001 appears to regulate TLR-related inflammatory pathways, NADPH oxidase-related pathways, and Rac1 inhibition. We speculate that the inhibitory effects of RCI001 on Rac1 mediate suppression of the NLRP3 inflammasome/IL-1β pathway, implicated in ROS generation via NADPH oxidase or TLR-related NF-κB activation ( 21 , 23 ) ( Figure 7 , presumed mechanism of RCI001 on the NLRP3 pathway). RCI001 was shown to modulate the activation of MAPK, ERK, and STAT pathways in the ocular alkali burn model ( 5 ).…”

Mushroom Natural Products in Neurodegenerative Disease Drug Discovery

“…As previously mentioned, NLRP3 inflammasome activation is gaining increasing interest as a drug target and in screening assays as it is a main driver of pyroptosis as described in Section 2 for microglial activation and as depicted in Figure 2 with the cleavage of GSDM and pore formation [ 65 , 70 , 147 ]. Sohaib et al (2021) have developed a new high-throughput screening assay that can be used to test inhibitors of NLRP3 inflammasome activation using immortalized bone marrow-derived macrophages (iBMDMs) [ 137 ].…”