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

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-ß1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1ß 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.

Role of microglia M1/M2 polarisation in the paraventricular nucleus: New insight into the development of stress-induced hypertension in rats.

The lack of precise therapies for stress-induced hypertension highlights the need to explore the process of blood pressure changes. Studies have shown that neuroinflammation in the central nervous system is associated with hypertension, although the mechanisms remain elusive. Microglia, are known to play dualistic protective and destructive roles, representing logical but challenging targets for improving stress-induced hypertension. Here, as a model, we used rats with stress-induced hypertension, and found that a switch from an immunoregulatory (M2) to a pro-inflammatory (M1) dominant response occurred in microglia during development of stress-induced hypertension. Administration of minocycline, which is commonly used to inhibit microglial M1 polarisation, attenuated the increase in activated microglia and M1 microglial markers expression in the hypothalamic paraventricular nucleus of rats with stress-induced hypertension. To shed further light on development of stress-induced hypertension, we examined changes in pro- and anti-inflammatory cytokines, and found increased expression of M2 microglial markers during early pathogenesis. Based on these results, we propose the possibility that M1/M2 microglia are related to development of stress-induced hypertension. Consequently, a target molecule that skews M2 polarisation of microglia may be a beneficial therapy for this disease.