2. Academic Validation
  3. JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

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

  • Brain Res Bull. 2022 Oct 15:189:174-183. doi: 10.1016/j.brainresbull.2022.09.007.
Xiaolin Zhong 1,  Zuyao Chen 2,  Yajuan Wang 3,  Mingli Mao 1,  Yingcheng Deng 4,  Mengmeng Shi 4,  Yang Xu 5,  Ling Chen 6,  Wenyu Cao 7
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Department of Endocrinology and Metabolism, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
  • 2 The First Affiliated Hospital, Department of Otorhinolaryngology, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
  • 3 The First Affiliated Hospital, Department of Laboratory Medicine, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
  • 4 Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
  • 5 Institute of Neuroscience, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
  • 6 The First Affiliated Hospital, Department of Endocrinology and Metabolism, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China. Electronic address: [email protected].
  • 7 Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China. Electronic address: [email protected].
PMID: 36100190 DOI: 10.1016/j.brainresbull.2022.09.007
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 phospho-nuclear factor kappa B (p-NF-κB) 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.

Keywords

Bromo and Extra-Terminal (BET) protein; JQ1; Neuroinflammation; Pyroptosis; Sepsis-associated encephalopathy (SAE).

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