The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. MCC950 blocks canonical and noncanonical NLRP3 activation at nanomolar concentrations, MCC950 also specifically inhibits activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasome. Further MCC950 reduces interleukin-1b (IL-1b) production in vivo and attenuates experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. MCC950 has displayed effective treatment in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle–Wells syndrome.1
The NLR family protein NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors2. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed the inflam¬masome. This results in the activation of caspase-1, which cleaves the proinflammatory cytokines IL-1β and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis.3 Other intracellular pattern recognition receptors (PRRs) are also capable of forming inflammasomes. These include other NLR family members such as NLRP1 and NLRC4, as well as non-NLR PRRs such as the double-stranded DNA (dsDNA) sensors absent in melanoma 2 (AIM2) and interferon, gamma inducible protein 16 (IFI16).4 NLRP3-dependent IL-1β processing can also be activated by an indirect, non-canonical pathway downstream of caspase-11.5
MCC950; NLRP3; NLRP3 inhibitor; NLRP3-dependent mouse model; cryopyrin-associated periodic syndrome; CAPS; NLRP3-associated syndromes; autoinflammatory; autoimmune diseases; NLRP3 inflammasome; apoptosis-associated speck-like protein; CARD; ASC; cysteine protease; caspase-1; inflam¬masome; proinflammatory cytokines; IL-1β; IL-18; pyroptosis; pattern recognition receptors (PRRs); NLRP1; NLRC4; non-NLR PRRs; melanoma 2; AIM2; interferon; gamma inducible protein 16; IFI16; NLRP3-dependent; IL-1β processing; caspase-11; NOD-like receptor; NLR family; pyrin domain–containing protein 3 (NLRP3) inflammasome; inflammatory process; multiple sclerosis; type 2 diabetes; Alzheimer’s disease; atherosclerosis; experimental autoimmune encephalomyelitis; EAE; multiple sclerosis; Muckle–Wells syndrome.
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