JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

Abstract

Sepsis-associated encephalopathy (SAE) manifests clinically in hyperneuroinflammation. Pyroptosis, which can induce an inflammatory cascade response, has been considered to be a causative factor of SAE. Evidence has shown that the bromo- and extraterminal (BET) proteins (including BRD2, BRD3, BRD4 and BRDT) inhibitor JQ1 can inhibit inflammation and suppress pyroptosis in various diseases. Therefore, we examined the effect of JQ1 on inflammasome-induced pyroptosis in the hippocampus in a mouse model of sepsis induced by lipopolysaccharide (LPS) injection. The results showed that JQ1 treatment alleviated sepsis-related symptoms, protected the blood–brain barrier (BBB), as indicated by upregulated expression of the tight junction proteins occludin and ZO-1, and remarkably rescued neuronal damage in SAE mice. Mechanistically, we demonstrated that JQ1 intervention inhibited the expression of BRD proteins and decreased the expression of inflammasomes by blocking nuclear factor kappa B (NFκB) signalling, attenuating the canonical pyroptosis (mediated by cleaved-Caspase1/11) pathway and the release of proinflammatory factors in the hippocampus of septic mice. Interestingly, we also found that JQ1 selectively suppressed the activation of hippocampal microglia in SAE mice. Thus, JQ1 protected the hippocampal BBB and neuronal damage through the attenuation of neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway induced by LPS injection in mice, and JQ1 may be a promising target for the prevention of SAE.

Microglial Activation: Key Players in SepsisAssociated Encephalopathy

“…Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction, which suggested that blocking IL-1 signaling attenuated the inflammatory cascade in response to LPS, thereby reducing microglial activation and preventing behavioral abnormalities [62]. Metformin can partially reverse the severe prognosis caused by sepsis by blocking microglial proliferation and inhibiting the production of inflammatory factors [72]. Cortistatin-14 is a neuropeptide structurally resembling somastostatin, which relieves anxiety-related behaviors in CLP mice, decreases the levels of various inflammatory cytokines, reduces sepsis-induced BBB disruption, and inhibits microglial activation [70].…”