Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation.

A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

Primiano MJ ，Lefker BA ，Bowman MR ，Bree AG ，Hubeau C ，Bonin PD ，Mangan M ，Dower K ，Monks BG ，Cushing L ，Wang S ，Guzova J ，Jiao A ，Lin LL ，Latz E ，Hepworth D ，Hall JP ... -  《-》

MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.

Vande Walle L ，Stowe IB ，Šácha P ，Lee BL ，Demon D ，Fossoul A ，Van Hauwermeiren F ，Saavedra PHV ，Šimon P ，Šubrt V ，Kostka L ，Stivala CE ，Pham VC ，Staben ST ，Yamazoe S ，Konvalinka J ，Kayagaki N ，Lamkanfi M ... -  《-》

Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death.

Matsuoka T ，Yoshimatsu G ，Sakata N ，Kawakami R ，Tanaka T ，Yamada T ，Yoshida Y ，Hasegawa S ，Kodama S ... -  《Scientific Reports》

The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages.

Finucane OM ，Sugrue J ，Rubio-Araiz A ，Guillot-Sestier MV ，Lynch MA ... -  《Scientific Reports》

The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice.

Cholestasis occurs in many clinical circumstances and leads to severe liver disorders. MCC950, a small-molecule NLRP3 inhibitor, was previously shown to have anti-inflammatory effects. However, these effects have not yet been examined in cholestatic liver injury. This study aimed to investigate the role of NLRP3 inflammasome and test the therapeutic efficacy and molecular mechanisms of MCC950 in cholestatic liver injury through the common bile duct ligation (BDL) model in mice. The influence of MCC950 on histological changes, levels of liver damage, neutrophil infiltration, liver cell death, inflammatory cytokine levels, and NLRP3 inflammasome expression were examined. The results of the current study confirmed that NLRP3 components were up-regulated during bile duct obstruction. MCC950 treatment significantly alleviated BDL-induced liver injury by reducing production of the pro-inflammatory cytokines IL-1β and IL-18 and inhibiting neutrophil infiltration and hepatic cell death. Moreover, MCC950 significantly inhibited NLRP3 activation during cholestatic liver injury. In addition, transcriptome analysis indicated that Toll-like receptor signaling may be involved in the protective effects of MCC950 in cholestatic liver injury. In conclusion, experimental findings demonstrate that MCC950 exerted protective effects in cholestatic liver injury and liver fibrosis by blocking NLRP3 inflammasome activation and the mechanism was partially attributed to inhibition of Toll-like receptor signaling. The present study indicates MCC950 could potentially be an effective therapeutic strategy for the treatment of cholestatic liver injury.

Qu J ，Yuan Z ，Wang G ，Wang X ，Li K ... -  《-》