HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway

Liao, Yuhe; Cheng, Jinbo; Kong, Xu; Li, Shuoshuo; Li, Xiaoheng; Zhang, Meijuan; Zhang, He; Yang, Tianli; Dong, Yuan; Li, Jun; Xu, Yun; Yuan, Zengqiang

doi:10.7150/thno.47651

Cited by 149 publications

(98 citation statements)

References 46 publications

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“…The inflammatory response is a major culprit and feature for the degree of I/R damage and is an important factor affecting iron accumulation in I/R 41 . A lack of oxygen and glucose could directly induce microglia activation and thereafter neuroinflammation 42 . In addition, evidence has shown that damaged or dead neuronal cells and excess ROS can activate an inflammatory response and upregulate pro-inflammatory gene expression after I/R injury 42 , 43 .…”

Section: Discussionmentioning

confidence: 99%

“…A lack of oxygen and glucose could directly induce microglia activation and thereafter neuroinflammation 42 . In addition, evidence has shown that damaged or dead neuronal cells and excess ROS can activate an inflammatory response and upregulate pro-inflammatory gene expression after I/R injury 42 , 43 . We observed upregulation of IL-6, strong activation of microglia and accompanying BBB disruption during ischaemic stroke (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis

et al. 2021

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Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis

et al. 2021

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“…In microglia, HDAC3, as a member of histone deacetylases, was found to be crucial for cGAS transcription by deacetylating p65 to enhance p65 association with cGAS promoter to transcriptionally potentiate cGAS expression. 71 …”

Section: Regulatory Mechanisms For Cgas Activity Controlmentioning

confidence: 99%

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Liu

2021

Sig Transduct Target Ther

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Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

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“…Hepatocytes do not express STING under normoxic conditions or after anoxia/reoxygenation. Histone deacetylase 3 (HDAC3) inhibition blocks ischemia-reperfusion-induced brain injury by inhibiting the microglial cGAS-STING signaling pathway ( 132 ). The cGAS-STING signaling activates in response to the cytosolic dsDNA, and HDAC3 promotes cGAS transcriptional expression in microglia during ischemia/reperfusion-induced brain injury.…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway

Cited by 149 publications

References 46 publications

Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis

Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

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