Let-7g* and miR-98 Reduce Stroke-Induced Production of Proinflammatory Cytokines in Mouse Brain

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 thirdleading 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.

Single-Cell RNA Sequencing With Combined Use of Bulk RNA Sequencing to Reveal Cell Heterogeneity and Molecular Changes at Acute Stage of Ischemic Stroke in Mouse Cortex Penumbra Area

“…This process occurs within 24 h. Peripheral macrophage polarization seems to be complete, in contrast to microglia cells, indicating that brain resident microglia and blood immune cells have different activation periods after an ischemic stroke. Infiltration and polarization of macrophages can be detected in early stages of stroke, facilitating inflammation progression ( Bernstein and Rom, 2020 ). Thus, interference with the initial peripheral immune cell recruitment may be an efficient measure to alleviate stroke inflammation; however, despite some improvement, the positive results from previous studies on this strategy were not significant ( Vogelgesang et al, 2019 ).…”

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

“…However, due to the different species and models used, different miRNAs are often screened out from high-throughput data. However, let-7 family is a common miRNA in these high-throughput data, indicating its core mechanism of ischemic stroke ( Bernstein and Rom, 2020 ; Chen et al, 2020 ). In our study, we found that two miRNAs from the same precursor, mml-let-7g-5p and mml-let-7g-3p_1ss22CT, had a special expression pattern and similar to the “miR-574 arm transition.” That is, the expression of mml-let-7g-5p was upregulated while that of mml-let-7g-3p_1ss22CT was downregulated in the same monkey.…”

“…It was previously shown that let-7 family regulate neuroinflammation in various pathologies, including spinal cord injury, multiple sclerosis, ischemic stroke, and Alzheimer’s disease ( Gaudet et al, 2018 ). Let-7g ∗ reduces the stroke-induced production of proinflammatory cytokines in the mouse brain ( Bernstein and Rom, 2020 ) and protects the blood–brain barrier under neuroinflammatory conditions ( Rom et al, 2015 ), while Let-7g counteracts endothelial dysfunction and ameliorates neurological functions in a mouse ischemia/reperfusion stroke model ( Bernstein et al, 2020 ). Furthermore, whether this conversion was significantly correlated with clinical ischemic stroke and the so-called “mml-let-7g arm transition” was involved in the pathological process needs further study.…”

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

“…They were all found to highly express in the mouse BMSC-EXOs in this study. let-7 is the rst discovered microRNA and functionally conserved in vertebrata [46], and was reported to inhibit production of proin ammatory cytokines such as Il8 and receptors such as Il1r1 and Il23r, to negatively regulate the differentiation of Th17 cell, and to regulate natural killer T cell [47][48][49]. Both EXOs and microRNAs are closely related to TGFβ signaling pathway when they play regulating roles.…”