Abstract
Stroke is a debilitating illness facing healthcare today, affecting over 800,000 people and causing over 140,000 deaths each year in the United States. Despite being the third-leading cause of death, very few treatments currently exist for stroke. Often, during an ischemic attack, the blood-brain barrier (BBB) is significantly damaged, which can lead to altered interactions with the immune system, and greatly worsen the damage from a stroke. The impaired, BBB promotes the infiltration of peripheral inflammatory cells into the brain, secreting deleterious mediators (cytokines/chemokines) and resulting in permanent barrier injury. let-7 microRNAs (miRs) are critical for regulating immune responses within the BBB, particularly after ischemic stroke. We have previously shown how transient stroke decreases expression of multiple let-7 miRs, and that restoration of expression confers significant neuroprotection, reduction in brain infiltration by neutrophils, monocytes and T cells. However, the specific mechanisms of action of let-7 miRs remain unexplored, though emerging evidence implicates a range of impacts on cytokines. In the current study, we evaluate the impacts of miR-98 and let-7g* on targeting of cytokine mRNAs, cytokine release following ischemic stroke, and cell-specific changes to the neurovascular space. We determined that miR-98 specifically targets IP-10, while let-7g* specifically aims IL-8, and attenuates their levels. Both produce strong impacts on CCL2 and CCL5. Further, let-7g* strongly improves neurovascular perfusion following ischemic stroke. Together, the results of the study indicate that let-7 miRs are critical for mediating endothelial-immune reactions and improving recovery following ischemic stroke.
Highlights
Stroke exerts a tremendous burden in lives, financial costs, and healthcare
We have shown that both let-7g* and miR-98 exert anti-inflammatory impacts on endothelial cells within the blood-brain barrier (BBB) (Rom et al, 2015; Bernstein et al, 2019, 2020) and reduce the damage caused by ischemic stroke
We determined that Transient Middle Cerebral Artery Occlusion (tMCAO) significantly increased the expression of IP-10 (p < 0.01), CXCL1 (p < 0.005), CXCL2 (p < 0.01), CCL2 (p < 0.01), CCL3 (p < 0.05), and CCL5 (p < 0.05) compared with baseline (Figures 1A–F)
Summary
Stroke exerts a tremendous burden in lives, financial costs, and healthcare. Over 800,000 people have strokes each year in the United States and over 140,000 of them will die as a result, representing roughly one death out of every 20. Stroke is a very expensive disease; the cost per hospitalization was ∼$20,000 in 2003–06 (Wang et al, 2014) and the total financial burden is estimated at 219 billion dollars each year (Yang et al, 2017) Despite such prevalence, very few treatments currently exist for stroke, and the ones that are available (namely tPA and mechanical thrombectomy), Let-7 MicroRNAs Diminish Cytokine Expression contain significant side effects and contraindications. Low or impaired expression is associated with greater cellular damage (Rom et al, 2015; Li et al, 2019), while increased expression of let-7 miRs is associated with improved cellular function (Zhang et al, 2016), and resistance to oxidative stress (Hou et al, 2012) Within this family, two miRs appear to be important for the vascular response to ischemic stroke: miR-98 and let-7g*. These are critical mediators of brain endothelial cells and are strongly downregulated during inflammatory events (Rom et al, 2015)
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