TY  - JOUR
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 poststroke immune blockade
T2  - Proceedings of the National Academy of Sciences
N2  - Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a “changing of the guards” between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73568
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-735686
SN  - 1091-6490
VL  - 117
IS  - 51
SP  - 32606
EP  - 32616
PB  - National Academy of Sciences
CY  - Washington, DC
ER  -