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Fine-tuning of microglia polarization prevents diabetes-associated cerebral atherosclerosis
Xuan Zhu1, Pengfei Xing1, Ping Zhang1
1Department of Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China.
Abstract:
Diabetes increases the occurrence and severity of atherosclerosis. When plaques form in brain vessels, cerebral atherosclerosis causes thickness, rigidity, and unstableness of cerebral artery walls, leading to severe complications like stroke and contributing to cognitive impairment. So far, the molecular mechanism underlying cerebral atherosclerosis is not determined. Moreover, effective intervention strategies are lacking. In this study, we showed that polarization of microglia, the resident macrophage in the central nervous system, appeared to play a critical role in the pathological progression of cerebral atherosclerosis. Microglia likely underwent an M2c-like polarization in an environment long exposed to high glucose. Experimental suppression of microglia M2c polarization was achieved through transduction of microglia with an adeno-associated virus (serotype AAV-PHP.B) carrying siRNA for interleukin-10 (IL-10) under the control of a microglia-specific TMEM119 promoter, which significantly attenuated diabetes-associated cerebral atherosclerosis in a mouse model. Thus, our study suggests a novel translational strategy to prevent diabetes-associated cerebral atherosclerosis through in vivo control of microglia polarization.
Insights
Diabetes-induced high glucose promotes M2c polarization in brain immune cells (microglia). Suppressing this specific polarization pathway significantly reduced cerebral atherosclerosis in a mouse model, offering a new prevention strategy.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Research
Background:
- Diabetes mellitus is a significant risk factor for atherosclerosis, particularly in cerebral vasculature.
- Cerebral atherosclerosis, characterized by plaque buildup in brain arteries, leads to stroke and cognitive decline.
- The precise molecular mechanisms driving diabetes-associated cerebral atherosclerosis remain largely undetermined.
Purpose of the Study:
- To investigate the role of microglia polarization in the pathogenesis of cerebral atherosclerosis under diabetic conditions.
- To explore the potential of targeting microglia polarization as a therapeutic strategy for diabetes-associated cerebral atherosclerosis.
Main Methods:
- Investigated microglia polarization in a mouse model of diabetes-associated cerebral atherosclerosis.
- Utilized adeno-associated virus (AAV-PHP.B) to deliver siRNA targeting interleukin-10 (IL-10) to microglia.
- Employed a microglia-specific TMEM119 promoter to control gene expression for targeted intervention.
Main Results:
- Identified M2c-like polarization of microglia in response to chronic high glucose environments.
- Demonstrated that experimental suppression of M2c microglia polarization significantly attenuated cerebral atherosclerosis.
- Showcased the efficacy of *in vivo* modulation of microglia polarization in a preclinical model.
Conclusions:
- Microglia polarization, specifically M2c phenotype, plays a critical role in diabetes-associated cerebral atherosclerosis progression.
- Targeting microglia M2c polarization presents a novel and promising translational strategy for preventing cerebral atherosclerosis in diabetic patients.
- This study highlights the potential of *in vivo* gene therapy for managing neurovascular complications of diabetes.
