TY  - INPR
A1  - Winek, Katarzyna
A1  - Lobentanzer, Sebastian
A1  - Nadorp, Bettina
A1  - Dubnov, Serafima
A1  - Dames, Claudia
A1  - Jagdmann, Sandra
A1  - Moshitzky, Gilli
A1  - Hotter, Benjamin
A1  - Meisel, Christian
A1  - Greenberg, David S.
A1  - Shifman, Sagiv
A1  - Klein, Jochen
A1  - Shenhar-Tsarfaty, Shani
A1  - Meisel, Andreas
A1  - Soreq, Hermona
T1  - Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade
T2  - medrxiv
N2  - 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.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75051
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-750514
UR  - https://www.medrxiv.org/content/10.1101/2020.07.02.20144212v1
VL  - Version 1
IS  - 2020.07.02.20144212 Version 1
ER  -