ACC1 (Acetyl Coenzyme A Carboxylase 1) Is a Potential Immune Modulatory Target of Cerebral Ischemic Stroke
| Autor: | Tingting Huang, Yuxi Zhou, Peiying Li, Weifeng Yu, Yan Li, Rolf Müller, Dan Tang, Xin Wang, Ziyu Zhu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell brain Calorie restriction Ischemia Inflammation Pharmacology Neuroprotection fatty acids regulatory T cells Brain Ischemia 03 medical and health sciences Mice 0302 clinical medicine Immune system medicine Animals Immunologic Factors Glycolysis Th17 cells Neuroinflammation 030304 developmental biology Caloric Restriction Advanced and Specialized Nursing Mice Knockout 0303 health sciences business.industry Infarction Middle Cerebral Artery glycolysis medicine.disease Mice Inbred C57BL Stroke medicine.anatomical_structure inflammation Neurology (clinical) Macrolides medicine.symptom Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery Acetyl-CoA Carboxylase |
| DOI: | 10.22028/d291-38469 |
| Popis: | Background and Purpose— Cerebral ischemic stroke elicits profound responses of CD4 + T cells, which in turn significantly affect the ischemic brain injury. ACC1 (acetyl coenzyme A carboxylase 1) is a key enzyme that has been recently found to propagate CD4 + T cell–associated inflammation by mediating de novo fatty acid synthesis; however, its role in the context of ischemic stroke remains unknown. Methods— Focal cerebral ischemia was induced by transient middle cerebral artery occlusion for 60 minutes in mice. Seahorse XF glycolysis assay and targeted lipidomic profiling were used to detect metabolic changes in CD4 + T cell after stroke. CD4 cre mice were crossed with ACC1 fl/fl mice to generate the CD4 + T-cell–specific deletion of ACC1 (CD4 cre ACC1 fl/fl mice) mice. Pretreatment with calorie restriction (CR; with 30% reduction of food for 4 weeks before middle cerebral artery occlusion) or post-treatment with ACC1 inhibitor, soraphen A were both used to test the effect of ACC1 modulation on poststroke neuroinflammation. Results— Cerebral ischemic stroke increased glycolysis and fatty acid synthesis in peripheral CD4 + T cells, in which the expression of ACC1 was also upregulated. CR downregulated the expression of ACC1 in CD4 + T cells after stroke. Both CD4 cre ACC1 fl/fl mice and CR-pretreated mice exhibited significantly reduced ischemic brain injury and preserved the balance of peripheral regulatory T cells/T helper 17 (Th17) cells. Furthermore, conditional knockout of ACC1 in CD4 + T cells attenuated the protection exerted by CR both on ischemic brain injury and peripheral balance of regulatory T cells/Th17 cells. Pharmacological inhibition of ACC1 after middle cerebral artery occlusion attenuates neuroinflammation, preserves regulatory T cells/Th17 balance, and improves neurological outcomes after ischemic stroke. Conclusions— ACC1 is a novel immune metabolic modulation target to balance the regulatory T cells and Th17 cells and blunt neuroinflammation after stroke. Inhibition of ACC1 can be a previously unrecognized mechanism that underlies CR-afforded neuroprotection against cerebral ischemic stroke. |
| Databáze: | OpenAIRE |
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