ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway

Han, Shichao; Li, Zhenzhen; Han, Fangfang; Jia, Yong; Qi, Lixin; Wu, Gaofeng; Cai, Wenju; Xu, Yongqiang; Liu, Cong; Zhang, Wanfu; Hu, Dahai

doi:10.1016/j.abb.2019.05.003

Cited by 22 publications

(21 citation statements)

References 33 publications

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“…Based on the above findings, one would expect that decreased Sirt1 leads to an increased expression of NF-κB in HF. Therefore, our aim was to determine if Sirt1 would be protective against HF through inhibiting the NF-κB p65 subunit, which is related to Sirt1 [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade

Lin

Zhao

et al. 2020

Aging

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Heart failure (HF) affects over 26 million people worldwide, yet the pathologies of this complex syndrome have not been completely understood. Here, we investigated the involvement of deacetylase Sirtuin 1 (Sirt1) in HF and its downstream signaling pathways. A HF model was induced by the ligation of the left coronary artery in rats, where factors associated with left ventricular echocardiography, heart hemodynamics and ventricular mass indexes were recorded. Collagen volume fraction in heart tissues was determined by Masson’s trichrome staining. Cell models of HF were also established (H 2 O 2 , 30 min) in cardiomyocytes harvested from suckling rats. HF rats presented with downregulated expressions of Sirt1, brain-derived neurotrophic factor (BDNF) and exhibited upregulated expressions of NF-κB p65 and miR-155. Repressed Sirt1 expression increased acetylation of NF-κB p65, resulting in the elevation of NF-κB p65 expression. NF-κB p65 silencing improved heart functions, decreased ventricular mass and reduced apoptosis in cardiomyocytes. MiR-155 inhibition upregulated its target gene BDNF, thereby reducing cardiomyocyte apoptosis. Sirt1 overexpression upregulated BDNF, improved heart function, and reduced apoptosis in cardiomyocytes. In conclusion, Sirt1 alleviates HF in rats through the NF-κB p65/miR-155/BDNF signaling cascade.

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Section: Introductionmentioning

confidence: 99%

Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade

Lin

Zhao

et al. 2020

Aging

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“…Further, RORα regulates the expression of Patterns recognition receptors (PRRs) upon the circadian rhythm [13]. Although the various functions of RORα as a negative regulator of the NF-κB signaling pathway have been shown [3,14], the molecular mechanisms associated with antitumor immunity remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Lee

Song

Kim

et al. 2020

Cancers

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Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8+ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.

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“…Indeed, while the signaling pathways impacted upon by RORα induces an anti-inflammatory role, the ability of RORα to alter the macrophage repertoire leads to the observed pro-inflammatory phenotype we have observed, as exemplified in reduced LPS responses in LysM Cre Rora fl/sg animals. Furthermore, while other studies have demonstrated an anti-inflammatory role for RORα in macrophages, it is important to note that this study focuses on primary macrophages isolated from animals deficient in functional RORα, while previous studies have focused on genetic manipulation of immortalized cells (6,29,30).…”

Section: Discussionmentioning

confidence: 99%

Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock

et al. 2021

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The transcription factor Related Orphan Receptor Alpha (RORα) plays an important role in regulating circadian rhythm, inflammation, metabolism and cellular development. Herein we show that in the absence of functional RORα in mice there is reduced susceptibility to LPS-induced endotoxic shock, with selective decreases in release of pro-inflammatory cytokines. Treatment of mice with a RORα selective synthetic inhibitor also reduced the severity of LPS-induced endotoxemia. The reduction in responses in Rora deficient mice was associated with an alterations in metabolic and pro-inflammatory functions of macrophages, both in vivo peritoneal macrophages and in vitro generated bone marrow derived macrophages. Using LysMCreRorafl/sg mice the reduced susceptibility to LPS was shown to be specific to Rora expression in the macrophages. This study identifies that Rora-mediated regulation of macrophages impacts on the pro-inflammatory responses elicited by LPS.

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ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway

Cited by 22 publications

References 33 publications

Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade

Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade

RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock

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