Inflammasomes & Inflammatory Diseases

Inflammasomes, first identified in 2002, are signaling platforms that mediate pathological inflammation and tissue damage. Key members of the inflammasome family include Absent In Melanoma 2 (AIM2), Pyrin, nucleotide-binding domain (NBD)-containing, leucine-rich repeat (LRR)-containing and pyrin domain (PYD)-containing protein 3 (NLRP3), NLRP6, neuronal apoptosis inhibitory protein (NAIP), NLRP1, and caspase activation and recruitment domain 8 (CARD8) ^[1].

The NLRP3 inflammasome is a megadalton complex; specifically, the 1.2 MDa NLRP3 inflammasome consists of NLRP3 monomers (comprising pyrin, NACHT, and LRR domains), NEK7, ASC, and pro-caspase-1. This inflammasome contributes to the pathogenesis of diverse diseases, including inflammatory disorders such as hereditary autoinflammatory diseases, ulcerative colitis, and arthritis. Activation of NLRP3 inflammasome triggers the activation of caspase-1, which in turn cleaves pro-interleukin (IL)-1β and pro-IL-18 into their biologically active forms. Caspase-1 also cleaves gasdermin D (GSDMD), generating pores in the cell membrane that facilitate the secretion of the pro-inflammatory cytokines IL-1β and IL-18. Conversely, inhibition of the NLRP3 inflammasome represents a promising therapeutic strategy for alleviating inflammatory diseases. To date, NLRP3 inhibitors have demonstrated efficacy in over 100 preclinical models of inflammatory diseases. For instance, Britannin-a small-molecule NLRP3 inhibitor-significantly attenuated NLRP3-mediated inflammation in mouse models of monosodium urate (MSU)-induced gouty arthritis and lipopolysaccharide (LPS)-induced acute lung injury (ALI), highlighting the therapeutic potential of targeting this pathway for inflammation resolution ^{[1] [2] [3] [4]}.

The advancement of NLRP3 inhibitors has further promoted research into targeting other inflammasome components for inflammatory disease treatment. The development of molecules that specifically target non-NLRP3 inflammasomes is expected to expand the therapeutic landscape for these disorders. Notably, the field of inflammasome inhibitors is advancing rapidly: the first potent inflammasome inhibitor was identified in 2015, and several NLRP3-targeting agents entered clinical trials in 2019. This progress underscores a promising future for inflammasome-based anti-inflammatory therapies ^[1].