Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage

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.

Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade

“…Microglial cells can damage neurons, oligodendrocytes, astrocytes and blood vessels in the early phase, releasing, e.g., ROS. However, in later stages, they may play a protective or repair role (M2 population) due to the release of TGF-beta1 (transforming growth factor beta 1), GDNF (glial cell derived neurotrophic factor) and the anti-inflammatory IL-10 (interleukin 10) (58)(59)(60).…”

The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage

“…Neuroinflammation is prevalent in these conditions and plays with similar mechanisms. In the early stage of both SAH and AIS, the activation of microglia by neutrophil is vital for following cascade of inflammation, with similar inflammatory mediators and pathways ( 120 ). Moreover, Tregs also play a major role in immunomodulatory function and neuroprotection after AIS ( 121 ).…”

Hypothermia Protects Against Ischemic Stroke Through Peroxisome-proliferator-activated-receptor Gamma

“…Microglial cells are widely activated by damage-associated molecular patterns released from injured neuronal cells, and subsequently, mediate drastic neuroin ammation during the acute stage of IS 26 . Previous studies have reported that de ciency of microglial cells inhibits the microglial cellmediated neuroin ammation, ultimately leading to the alleviation of IS in mouse models 27 . Our data showed that hypothermia suppressed the activation of microglial cells and shifts the polarization of microglial cells from pro-in ammatory phenotype to anti-in ammatory phenotype.…”