The Role of MicroRNAs on Systematic and Central Nervous System-Inflammation in Aged Mice

Advisors: Louise McCullough, MD, PhD and Jennifer Wargo, MD

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Meeting ID: 966 1501 4547
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MicroRNAs play a crucial role in multiple biological processes, including development, cell differentiation, proliferation, metabolism, and cell death. Aberrant regulation of microRNAs is seen in many diseases, such as sepsis, cardiovascular disease, neurological diseases such as stroke, and metabolic disorders. Because of their involvement in disease processes, microRNAs have been investigated as both potential biomarkers, and as therapeutic targets. Age-related inflammatory diseases including diabetes, obesity, and atherosclerosis are important risk factors for infection and sepsis. Intestinal barrier impairment occurs with aging and after brain injuries, including stroke.  Both aging and stroke increase the risk of infection and sepsis and are a common cause of death in stroke patients. There has been a paucity of research examining the impact of microRNAs on stroke-induced sepsis, specifically regarding their involvement in regulating intestinal barrier integrity. In a mouse model of sepsis generated via cecal ligation and puncture, we found altered microRNA profiles in intestinal epithelial cells that functionally regulate and shape the IEC-specific transcriptome. We found increased expression of 14 microRNAs, and a decrease in the expression of 9 microRNAs in intestinal epithelial cell with sepsis. The expression of several microRNAs, such as miR-149-5p, miR-466q, miR-495, and miR-511-3p, was increased with disrupted intestinal barriers, and IECs of septic mice regulated Wnt signaling in pathway analysis. Some of these altered miRNAs were noted to be key drivers of oxidative stress, apoptosis, and ischemia which may explain the heightened risk of sepsis in stroke patients. Collectively, it is evident that systemic inflammation is a contributing factor for the development of infection and sepsis.

It has also been increasingly recognized that individuals who experience feelings of loneliness or social isolation are more prone to acquiring infections and sepsis. Interestingly, these individuals also have a higher risk of stroke, and have poorer outcomes once a stroke occurs. Social isolation increases mortality and morbidity in patients with cerebrovascular diseases including ischemic stroke. Individuals aged 50 or above are more likely to have risk factors (i.e., loss of close family members, emerging sensory impairment, deteriorating health, and chronic neurodegenerative diseases) that contribute to social isolation and loneliness. Approximately, three-quarters of all patients with neurodegenerative diseases and stroke are over the age of 65, highlighting the importance of social isolation in outcomes in these elderly patients. Social isolation leads to increased inflammation and oxidative stress in peripheral tissues (i.e., higher pro-inflammatory cytokines) and in the brain (i.e., microglial activation and cognitive impairment) worsening post-stroke outcomes. MicroRNAs have been shown to regulate key microglial activation states in acute and chronic diseases, including ischemic stroke. Modulating these microRNAs can inhibit ischemia-induced microglial activation. The underlying mechanisms driving the detrimental effects of isolation are not fully understood but involve microRNA regulation. The significance of our study stems from this gap in knowledge. We examined the influence of post-stroke social isolation on microRNA profiles and determined the effects on microglial activation as a strategy for possible therapeutic intervention. Our study utilized aged mice to examine the functional roles of microRNAs as potential therapeutic targets to reverse social isolation-induced functional decline, systemic inflammation, and pro-inflammatory microglial activation in the post-stroke SI environment. We found that aged male mice subjected to 4 days of isolation after middle cerebral artery occlusion, a well-established experimental model of stroke, led to changes in microRNA profiles in the brain, including miR-142a-3p/5p, and miR-449a-5p, and miR-10a-5p. Collectively, downstream KEGG pathway analysis demonstrated that these microRNA targets regulated TLR, TNF, and PI3K-Akt signaling pathways that dictate microglial activation states. Aged mice subjected to social isolation after stroke were treated with an antagomir to miR-10a-5p, the most highly upregulated miRNA after post-stroke SI or a scrambled miRNA.  Treated mice had decreased anxiolytic phenotypes compared to mice that received the scrambled-miRNA control and showed improved behavioral outcomes to the level seen in pair-housed (PH) aged stroke mice. We then identified specific circulatory microRNAs that are differently expressed in men and women after stroke, and examined changes based on validated scales of social interaction (Lubben Social Network Scale) and loneliness (UCLA loneliness scale) as method of stratifying loneliness severity in stroke patients.

In conclusion, social isolation exacerbates stroke outcomes, and alters microRNA expression profiles, suggesting a potential interplay between social factors, inflammation, microRNA regulation, and microglial activation in stroke pathology. Understanding these intricate connections could offer insights into novel therapeutic targets for effective stroke management. Future studies investigating microglial-specific miRNAs in the context of post-stroke social isolation and how they exacerbate pro-inflammatory cytokine activation and cognitive impairment are warranted.

Advisory Committee:
Louise McCullough, MD, PhD, Chair
Jennifer Wargo, MD, Co-Chair
Huihui Fan, PhD
Juneyoung Lee, PhD
Paul Schulz, MD
Antonio Teixeria, MD, PhD
Pamela Wenzel, PhD