Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6 h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.

Xu X ，Yin D ，Ren H ，Gao W ，Li F ，Sun D ，Wu Y ，Zhou S ，Lyu L ，Yang M ，Xiong J ，Han L ，Jiang R ，Zhang J ... -  《-》

Inhibition of NLRP3 inflammasome alleviates cognitive deficits in a mouse model of anti-NMDAR encephalitis induced by active immunization.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disorder, characterized by cognitive deficits as one of its vital features. The nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome is a key contributor to neuroinflammation and cognitive deficits in neurological diseases. However, the underlying mechanism of anti-NMDAR encephalitis remains unclear, and the biological function of the NLRP3 inflammasome in this condition has not been elucidated. In this study, a mouse model of anti-NMDAR encephalitis was induced by active immunization with the GluN1356-385 peptide (NEA model). The NLRP3 inflammasome in the hippocampus and temporal cortex was investigated using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence staining. The impact of MCC950 on cognitive function and NLRP3 inflammation was assessed. Confocal immunofluorescence staining and Sholl analysis were employed to examine the function and morphology of microglia. In the current study, we discovered overactivation of the NLRP3 inflammasome and an enhanced inflammatory response in the NEA model, particularly in the hippocampus and temporal cortex. Furthermore, significant cognitive dysfunction was observed in the NEA model. While, MCC950, a selective inhibitor of the NLRP3 inflammasome, sharply attenuated the inflammatory response in mice, leading to mitigated cognitive deficits of mice and more regular arrangements of neurons and reduced number of hyperchromatic cells were also observed in the hippocampus area. In addition, we found that the excess elevation of NLRP3 inflammasome was mainly expressed in microglia accompanied with the overactivation of microglia, while MCC950 treatment significantly inhibited the increased number and activated morphological changes of microglia in the NEA model. Altogether, our study reveals the vital role of overactivated NLRP3 signaling pathway in aggravating the inflammatory response and cognitive deficits and the potential protective effect of MCC950 in anti-NMDAR encephalitis. Thus, MCC950 represents a promising strategy for anti-inflammation in anti-NMDAR encephalitis and our study lays a theoretical foundation for it to become a clinically targeted drug.

Yang X ，Sun A ，Kong L ，Yang X ，Zhao X ，Wang S ... -  《-》

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 ... -  《-》

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》

Rapamycin improves the neuroprotection effect of inhibition of NLRP3 inflammasome activation after TBI.

Chen Y ，Meng J ，Xu Q ，Long T ，Bi F ，Chang C ，Liu W ... -  《-》