Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway

Abstract

BackgroundThe NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been identified as an important mediator of blood–brain-barrier disruption in sepsis-associated encephalopathy (SAE). However, no information is available concerning the critical upstream regulators of SAE.MethodsLipopolysaccharide (LPS) was used to establish an in vitro model of blood–brain barrier (BBB) disruption and an in vivo model of SAE. Disruption of BBB integrity was assessed by measuring the expression levels of tight-junction proteins. NLRP3 inflammasome activation, pro-inflammatory cytokines levels, and neuroapoptosis were measured using biochemical assays. Finally, the FITC-dextran Transwell assay and Evan’s blue dye assay were used to assess the effect of Maf1 on LPS-induced endothelial permeability in vitro and in vivo.ResultsWe found that Maf1 significantly suppressed the brain inflammatory response and neuroapoptosis induced by LPS in vivo and in vitro. Notably, Maf1 downregulated activation of the NF-κB/p65-induced NLRP3 inflammasome and the expression of pro-inflammatory cytokines. In addition, we found that Maf1 and p65 directly bound to the NLRP3 gene promoter region and competitively regulated the function of NLRP3 in inflammations. Moreover, overexpression of NLRP3 reversed the effects of p65 on BBB integrity, apoptosis, and inflammation in response to LPS. Our study revealed novel role for Maf1 in regulating NF-κB-mediated inflammasome formation, which plays a prominent role in SAE.ConclusionsRegulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.

Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy

“…Nod-like receptor protein 3 (NLRP3) plays an important role in the inflammation cascade by amplifying the inflammation response ( Islam et al, 2020 ). Chen et al found a suppression of the NF-kB/NLRP3 inflammatory pathway by directly binding to the promoter region of NLRP3, which resulted in a decreased cell apoptosis and inflammation, and an alleviation of BBB disruption and SAE ( Chen et al, 2020 ). Kikuchi et al showed that inhibition of poldip2 could attenuate BBB disruption caused by sepsis by regulating the nuclear translocation process of NF-κB as well as Cox-2 expression, preventing the occurrence and development of SAE ( Kikuchi et al, 2019 ) ( Figure 2 ).…”

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons

“…Nuclear factor-kappa B (NF- κ B) is a widely studied transcription factor that is involved in many physiological processes, such as regulating multiple aspects of innate and adaptive immune function [ 17 , 18 ], and as a key mediator of the inflammatory response in regulating inflammatory pain [ 19 ], neuropathic pain [ 20 ], and other chronic pain [ 21 ]. Recent studies have shown that NF- κ B participates in the inflammatory cascade by activating the Nod-like receptor protein 3 (NLRP3) inflammasome in the nucleus [ 22 , 23 ]. The activation of inflammasomes contributes to the development of chronic pain [ 24 , 25 ].…”

Therapeutic effects of human umbilical cord mesenchymal stem cell on sepsis-associated encephalopathy in mice by regulating PI3K/AKT pathway

“…Morris water maze test was carried out to evaluate mice's neurological dysfunction as previously described [14][15][16]. The water maze consisted of a circular black pool (100 cm diameter, 38 cm deep), and it was filled with opaque water (25 cm deep).…”