BackgroundHigh-fat feeding and hyperglycemia, key risk factors for the development of metabolic syndrome (MetS), are emerging to associate with increased risk of developing dementia and cognitive decline. Despite this, clinical and experimental studies have yet to elucidate the specific contributions of either high-fat feeding or hyperglycemia to potential neuroinflammatory components. In this study, we delineate these individual components of MetS in the development of neuroinflammation.MethodsMale C57Bl/6 J adult mice were treated with either citrate vehicle (CIT) or streptozotocin (STZ; 55 mg/kg) 3, 5 and 7 days before commencement of either a normal or high-fat diet for 9 or 18 weeks. By creating separate models of high-fat feeding, STZ-induced hyperglycemia, as well as in combination, we were able to delineate the specific effects of a high-fat diet and hyperglycemia on the brain. Throughout the feeding regime, we measured the animals’ body weight and fasting blood glucose levels. At the experimental endpoint, we assessed plasma levels of insulin, glycated haemoglobin and performed glucose tolerance testing. In addition, we examined the effect of high fat-feeding and hyperglycemia on the levels of systemic inflammatory cytokines, gliosis in the hippocampus and immune infiltration in cerebral hemispheric tissue. Furthermore, we used intravital multiphoton microscopy to assess leukocyte-endothelial cell interactions in the cerebral vasculature of mice in vivo.ResultsWe showed that acute hyperglycemia induces regional-specific effects on the brain by elevating microglial numbers and promotes astrocytosis in the hippocampus. In addition, we demonstrated that chronic hyperglycemia supported the recruitment of peripheral GR1+ granulocytes to the cerebral microvasculature in vivo. Moreover, we provided evidence that these changes were independent of the systemic inflammation associated with high-fat feeding.ConclusionsHyperglycemia alone preferentially induces microglial numbers and astrocytosis in the hippocampus and is associated with the peripheral recruitment of leukocytes to the cerebrovasculature, but not systemic inflammation. High-fat feeding alone, and in combination with hyperglycemia, increases the systemic pro-inflammatory cytokine milieu but does not result in brain-specific immune gliosis. These results shed light on the specific contributions of high-fat feeding and hyperglycemia as key factors of MetS in the development of neuroinflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1329-8) contains supplementary material, which is available to authorized users.
Clinical trials involving the blockage of peripheral inflammatory leukocyte recruitment into the brain have puzzlingly led to either no significant improvement in stroke outcome, or even worsened outcomes and increased mortality, prompting a re-evaluation of our understanding into the neuroinflammatory processes after stroke. Whilst traditionally understood as simple effectors of the innate immune system, emerging research in vascular disease biology has redefined the neutrophil as a specialized and highly specific cell type with dynamic functional capacity. Indeed, emerging experimental evidence indicates that neutrophils display diverse roles in the acute stages of ischemic stroke with the ability to elicit both pro-inflammatory and antiinflammatory effects. Currently, there is some uncertainty as to whether neutrophil diversity is beneficial or harmful in stroke as their interactions with the resident cells of the brain, such as microglia and neurons, would potentially elicit heterogeneous outcomes. Current treatments for patients with stroke aim to remove the vascular blockage and to restore blood flow, but there are currently no drug treatments for managing the loss of functional brain tissue nor restoration of microglial and neuronal damage. If these hypothesized wound-healing functions of neutrophils can be validated in a stroke setting, promoting the recruitment of this type of neutrophils into the injured brain tissue may form a promising therapeutic target for the majority of stroke patients currently without treatment. In this review, we will provide an update on recent research that has explored neutrophil heterogeneity in the neuroinflammatory cascade after ischemic stroke.
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