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

Yu, Shuyou; Fu, Jiaying; Wang, Jian; Zhao, Yuanxin; Liu, Buhan; Wei, Jiahang; Yan, Xiaoyu; Su, Jing

doi:10.3390/ijms23010135

Cited by 16 publications

(8 citation statements)

References 171 publications

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“…This is the first report on the effect of GL on improving glucose uptake after cerebral ischemia. Recent research has shown [ 31 ] that improvements in the energy utilization status of brain tissue can modulate the polarization of microglia. M1 microglia are activated by canonical activation pathway LPS/IFN- γ , and their main metabolic pathways are anaerobic glycolysis and pentose phosphate, whilst M2 microglia are activated by IL-4/IL-13 and have an intact tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) process with prominent fatty acid synthesis and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Gualou Guizhi Decoction Improves Glucose Metabolism and Alleviates Microglia-Associated Inflammation after Cerebral Ischemia

Zhang

Han

Zou

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. The classical prescription Gualou Guizhi decoction (GL), a mixture of Radix Trichosanthis, Ramulus Cinnamomi, Radix Paeoniae Alba, Radix Glycyrrhizae, Zingiberis Rhizoma Recens, and Fructus Ziziphus Jujuba, was clinically used in the treatment of limb spasms after stroke and has achieved remarkable therapeutic effects. However, the underlying mechanism still needs to be further explored. Methods. Cerebral ischemia/reperfusion (CI/R) in Sprague-Dawley rats was induced by middle cerebral artery occlusion followed by filament removal. GL was intragastrically administered once daily for 7 or 14 consecutive days. The effect of GL on neurobehavioral impairment was evaluated. 18F-FDG micro-PET imaging was used to detect the effects of GL on glucose utilization in neural cells after CI/R. Immunohistochemical staining of glucose transporter 1 (Glut-1), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule-1 (Iba-1) was further performed to show the effects of GL on cerebral glucose transport and the activation of inflammatory-related glial cells. Markers related to the microglial subtype were also assessed to investigate the effects of GL on microglia polarization. Results. Neurological deficits induced by CI/R were significantly improved by GL administration. GL restored the glucose uptake in the ischemic hemisphere. Glut-1, the major glucose transporter in the brain, was significantly increased after GL treatment. Moreover, GL mitigated the activation of astrocytes and microglia after CI/R. Furthermore, GL significantly decreased proinflammatory M1-type microglial markers TNF-α and iNOS, while increasing anti-inflammatory M2 microglial markers CD206 and Arg-1. Conclusion. GL enhanced the uptake and utilization of glucose in neural cells after CI/R. It exerted significant anti-inflammatory effects by regulating the polarization of microglia. These results provided further evidence supporting the clinical application of GL in the treatment of cerebral ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Gualou Guizhi Decoction Improves Glucose Metabolism and Alleviates Microglia-Associated Inflammation after Cerebral Ischemia

Zhang

Han

Zou

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Various metabolic processes are associated with cerebral ischemia-reperfusion injury-induced brain tissue damage [43][44][45] . Therefore, we estimated the metabolic status of various cell compositions in different groups based on their expression pro les.…”

Section: Lrg1 Knockout Alters the Metabolic Status Of Multiple Cell P...mentioning

confidence: 99%

Single-Cell RNA Sequencing Unveils Lrg1's Role in Cerebral Ischemia‒Reperfusion Injury by Modulating Various Cells

Ruan

Cao

Qian

et al. 2023

Preprint

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Background and purpose: Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown. Methods: Wild-type (WT) and Lrg1 knockout (Lrg1-/-) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout. Results: Lrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1-/- mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) permeability by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death. Conclusions: Convincing evidence has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

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“…Mitochondrial DNA oxidation is considered another requirement for inflammasome activation; although more recent evidence has refuted the above hypothesis considering that both mtROS and mitochondrial dysfunction do not appear to be indispensable in determining the phlogistic activation of inflammasome [ 78 ].…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

et al. 2022

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Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study.

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

Cited by 16 publications

References 171 publications

Gualou Guizhi Decoction Improves Glucose Metabolism and Alleviates Microglia-Associated Inflammation after Cerebral Ischemia

Gualou Guizhi Decoction Improves Glucose Metabolism and Alleviates Microglia-Associated Inflammation after Cerebral Ischemia

Single-Cell RNA Sequencing Unveils Lrg1's Role in Cerebral Ischemia‒Reperfusion Injury by Modulating Various Cells

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

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