NLRP3 Inflammasome: A Novel Therapeutic Target in Arthritis

Abstract

Pyroptosis induction requires two types of receptors that sense harmful signals which can be given off by invasive pathogens or by an injury to a tissue. These receptors are Nod-like receptors (NLRs) and Toll-like receptors [7]. The nucleotide binding domain and leucinerich repeat pyrin 3 domain (NLRP3 or cryopyrin) sensor protein, organizes the assembly of the best-characterized inflammasome, the NLRP3-inflammasome. NLRP3 is kept in an inactive state complexed with Heat Shock Protein 90 (HSP90) and suppressor of the G2 allele of skp1 (SGT1) in the cytoplasm. Upon detecting harmful signals, HSP90 and SGT1 are released from NLRP3 which then recruits apoptosisassociated speck-like protein containing a CARD (ASC) protein and caspase-1 to the inflammasome complex. ASC contains a caspase activation and recruitment domain (CARD) that binds and facilitates activation of pro-caspase-1 through CARD-CARD interactions. Activated caspase-1 cleaves the precursors of interleukin (IL)-1β and IL-18 converting them into the mature, secreted inflammatory cytokines [8]. Furthermore, the inflammatory caspases 1, 4 and 5 can induce pyroptosis directly by cleaving gasdermin D (GSDMD) into a pore-forming amino-terminal domain (GSDMDN) and an inhibitory carboxy-terminal (GSDMDC) domain. GSDMDN then oligomerizes and inserts in the plasma membrane inducing rapid cell lysis [9-12].