Ting Li1, Jin Zhao1, Wenguang Xie1, Wanru Yuan1, Jing Guo1, Shengru Pang1, Wen-Biao Gan2, Diego Gómez-Nicola3, Shengxiang Zhang4. 1. Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China. 2. Molecular Neurobiology Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, 10016, USA. wenbiao.gan@nyumc.org. 3. Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840 LD80C, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. D.Gomez-Nicola@soton.ac.uk. 4. Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China. sxzhang@lzu.edu.cn.
Abstract
BACKGROUND: Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke. METHODS: A Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTR mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors. RESULTS: The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke. CONCLUSIONS: These results suggest that activated microglia is an important modulator of the brain's inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
BACKGROUND: Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke. METHODS: A Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTR mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors. RESULTS: The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke. CONCLUSIONS: These results suggest that activated microglia is an important modulator of the brain's inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
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