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Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade
(2020)
Stroke is a leading cause of death and disability. Recovery depends on balance between inflammatory response and immune suppression, which can be CNS-protective but may worsen prognosis by increasing patients’ susceptibility to infections. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Therefore, we sought small RNA balancers of the cholinergic anti-inflammatory pathway in peripheral blood from ischemic stroke patients. Using RNA-sequencing and RT-qPCR, we discovered in patients’ blood on day 2 after stroke a “change of guards” reflected in massive decreases in microRNAs (miRs) and increases in transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent small RNA-sequencing datasets presented post-stroke enriched tRFs as originating from lymphocytes and monocytes. In these immune compartments, we found CD14+ monocytes to express the highest amounts of cholinergic transcripts. In-depth analysis of CD14+ regulatory circuits revealed minimally overlapping subsets of transcription factors carrying complementary motifs to miRs or tRFs, indicating different roles for the stroke-perturbed members of these small RNA species. Furthermore, LPS-stimulated murine RAW264.7 cells presented dexamethasone-suppressible upregulation of the top 6 tRFs identified in human patients, indicating an evolutionarily conserved and pharmaceutically treatable tRF response to inflammatory cues. Our findings identify tRF/miR subgroups which may co-modulate the homeostatic response to stroke in patients’ blood and open novel venues for establishing RNA-targeted concepts for post-stroke diagnosis and therapeutics.
RNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male- and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.
Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer’s disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a “cocktail” containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the “cocktail” which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.