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.