Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR‐127 in aged animals

Abstract

Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke‐induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron‐specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co‐existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR‐127, that is highly neuronal, to be associated with increased cell death in the aged, LPS‐injected ischemic mice. Target prediction tools indicate that miR‐127 interacts with several basally expressed neuronal genes, and of these we verify miR‐127 binding to Psmd3. Finally, we report reduced expression of miR‐127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.

Role of MicroRNAs and Long Non-Coding RNAs in Sarcopenia

“…This implies that miR-127 functions as an activator of cell differentiation and a suppressor of cell proliferation. Interestingly, the expression levels of miR-127 were also downregulated in the brains of aged mice, implying that miR-127 contributes to age-related defects or diseases [ 116 ]. Although not many studies have explored the function of miR-434-3p, it has been recently reported that circulating miRNA levels are decreased in patients with sarcopenia accompanied by chronic heart failure [ 117 ].…”

ciRS-7 and miR-7 regulate ischemia induced neuronal death via glutamatergic signaling

“…Further processing, in all cases from -5p arm, give rise to two mature miR-7 sequences (miR-7a and miR-7b), differing only by a single nucleotide in the non-seed position number 10 (Figure 2C). To study the expression of the three miR-7 loci in our system, we utilized Global runon sequencing (GRO-seq), which enable the capture of nuclear nascent RNA primary molecules, and compared the expression in our murine culture 22 with different mouse tissues and cell lines [22][23][24][25][26][27][28][29][30][31][32] (Supplementary Table S3). In physiological conditions, only cortical neurons and the pituitary gland actively transcribe all three independently regulated miR-7 loci (Figure 2D, Supplementary figure S3).…”

The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging

“…Proteasomal activity decreases during normal aging and in neurodegeneration [ 80 ]. Within the last year, two studies have described the contribution of miRNA regulation on UPS-related alterations throughout aging in the non-disease context [ 81 , 82 , 83 ]. For example, miR-127-5p was found to have reduced expression in the brains of aged C57BL/6J mice undergoing LPS-induced ischemia, and for the first time, identified 26S proteasome non-ATPase regulatory subunit 3 (Psmd3) as one of its targets [ 82 ].…”

“…Within the last year, two studies have described the contribution of miRNA regulation on UPS-related alterations throughout aging in the non-disease context [ 81 , 82 , 83 ]. For example, miR-127-5p was found to have reduced expression in the brains of aged C57BL/6J mice undergoing LPS-induced ischemia, and for the first time, identified 26S proteasome non-ATPase regulatory subunit 3 (Psmd3) as one of its targets [ 82 ]. This study is important because the authors not only provided a brain miRNome through mature miRNA sequencing but also identified a novel miRNA in the brain, miR-127, which is associated with cell apoptosis and proteasomal activity during aging and ischemia.…”