25-Hydroxycholesterol protecting from cerebral ischemia-reperfusion injury through the inhibition of STING activity

Abstract

Middle cerebral artery occlusion (MCAO) injury refers to impaired blood supply to the brain that is caused by a cerebrovascular disease, resulting in local brain tissue ischemia, hypoxic necrosis, and rapid neurological impairment. Nevertheless, the mechanisms involved are unclear, and pharmacological interventions are lacking. 25-Hydroxycholesterol (25-HC) was reported to be involved in cholesterol and lipid metabolism as an oxysterol molecule. This study aimed to determine whether 25-HC exerts a cerebral protective effect on MCAO injury and investigate its potential mechanism. 25-HC was administered prior to reperfusion in a mouse model of MCAO injury. 25-HC evidently decreased infarct size induced by MCAO and enhanced brain function. It reduced stimulator of interferon gene (STING) activity and regulated mTOR to inhibit autophagy and induce cerebral ischemia tolerance. Thus, 25-HC improved MCAO injury through the STING channel. As indicated in this preliminary study, 25-HC improved MCAO injury by inhibiting STING activity and autophagy as well as by reducing brain nerve cell apoptosis. Thus, it is a potential treatment drug for brain injury.

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

“…Senescent cells display a strong proinflammatory secretion profile, which is widely consistent across various stages of senescence and biological sources [ 31 , 144 , 145 , 146 ]. SASP supports non-cell autonomous tumor suppression through cell cycle arrest of lesioned and malignant cells and by attracting immune cells to their destruction.…”

“…This complex secretome is directed by the activation of multiple signaling pathways, such as mitogen-activated protein kinase (MAPK) signaling, mammalian target of rapamycin (mTOR), GATA4/p62 intermediated autophagy, and the phosphoinositide 3 kinase (PI3K) pathways [ 152 ]. All of these cascades converge on the stimulation of NF-κB and C/EBPβ pathways, orchestrating the dynamics of the complex SASP secretome [ 144 , 146 , 153 , 154 , 155 ]. This huge variety of possible targets responsible for regulating the cascades, leading to the senescence associated secretory phenotype, incited the creation of different molecules and antibodies to interact either with NF-κB and C/EBPβ transcriptional activities at different levels [ 144 , 146 , 153 , 154 , 155 ], or with specific components of SASP to mitigate the deleterious effects of SASP.…”

“…All of these cascades converge on the stimulation of NF-κB and C/EBPβ pathways, orchestrating the dynamics of the complex SASP secretome [ 144 , 146 , 153 , 154 , 155 ]. This huge variety of possible targets responsible for regulating the cascades, leading to the senescence associated secretory phenotype, incited the creation of different molecules and antibodies to interact either with NF-κB and C/EBPβ transcriptional activities at different levels [ 144 , 146 , 153 , 154 , 155 ], or with specific components of SASP to mitigate the deleterious effects of SASP. There is a compendium of available inhibitors with the ability to attenuate SASP effects in vivo and perhaps minimize the negative consequences of senescent cells.…”

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

“…However, this impairment of synaptic plasticity may be refl ection of the general protective function of 25-HC secreted by the microglia. Indeed, 25-HC signifi cantly reduced apoptotic loss of neurons caused by the overexpression of the pro-infl ammatory regulator STING (stimulator of interferon genes) and autophagy following cerebral artery oc-clusion [76]. 25-HC rapidly suppresses translocation of the IFNγ receptors into lipid rafts and subsequent activation of these receptors; as a result, 25-HC causes a decrease in the IFNγ-mediated production of pro-infl ammatory cytokines by the microglia [14].…”

The Influence of Mitochondrial-DNA-Driven Inflammation Pathways on Macrophage Polarization: A New Perspective for Targeted Immunometabolic Therapy in Cerebral Ischemia-Reperfusion Injury

“…This reduces the neuroinflammatory response. Therefore, increasing the degradation of STING from the autophagy or proteasome pathway can effectively reduce the damage after ischemia and revascularization [ 156 ]. Shen et al believe that microRNA-24-3p reduces liver ischemia-reperfusion injury in mice by inhibiting STING signaling [ 157 ].…”