JQ1 Attenuates Neuroinflammation by Inhibiting Inflammasome-Dependent Canonical Pyroptosis Pathway in Sepsis-Associated Encephalopathy

Abstract Sepsis-associated encephalopathy (SAE) is manifested clinically in hyperneuroinflammation and associated with increased morbidity worldwide. Pyroptosis, a novel programmed cell death, has been considered as a causative factor of SAE. Bromodomain-containing protein 4 (BRD4) is a member of the Bromo and Extra-Terminal (BET) family, and promotes inflammatory response in various diseases. Thereby, we examined the effect of JQ1, which is a specific selective inhibitor of BRD4, on the inflammasome-induced pyroptosis of hippocampus in sepsis mice model induced by lipopolysaccharide (LPS) treatment. And we found that JQ1 treatment inhibited the phosphorylation of BRD4, alleviated weight loss and splenomegaly, as well as decreased the serum levels of procalcitonin (PCT) and D-lactate dehydrogenase (D-LDH) induced by LPS injection. Moreover, JQ1 administration decreased the expression of nod-like receptor family protein 1 (NLRP1) or 3 (NLRP3) or the absent in melanoma 2 (Aim2) inflammasomes by blocking nuclear factor kappa B (NFκB) signaling in the hippocampus of sepsis mice. Interestingly, we found that JQ1 selectively attenuated the canonical pyroptosis pathway in SAE mice, indicating by reduced expression of Caspase-1, Caspase-11, gasdermin D (GSDMD) and gasdermin A (GSDMA). JQ1 intervention also suppressed the activation of hippocampal microglia and the release of pro-inflammatory factors, such as IL-1β, IL-18 and IL-6 in SAE mice. In addition, JQ1 treatment protected blood brain barrier (BBB) by up-regulated the expression of tight junction protein occludin and ZO-1 in SAE mice. Furthermore, JQ1 administration remarkably rescued neuronal damage in SAE mice, as enhanced expression of hippocampal NeuN and Doublecortin (DCX). Thus, the protective effects of BRD4 inhibitor JQ1 on SAE were verified in neurons via the inhibition of canonical pyroptosis induced inflammation.