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 post-stroke immune blockade
T2  - medrxiv
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 two days 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 RT-qPCR validated the top 6 upregulated 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 upregulated the top 6 stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using an ssRNA mimic induced downregulation of immune regulator Z-DNA binding protein 1 (Zbp1). In summary, we identified a “changing of the guards” between RNA types that may systemically affect homeostasis in post-stroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein- and RNA-level.

Significance Statement Ischemic stroke triggers peripheral immunosuppression, increasing the susceptibility to post-stroke pneumonia that is linked with poor survival. The post-stroke brain initiates intensive communication with the immune system, and acetylcholine contributes to these messages; but the responsible molecules are yet unknown. We discovered a “changing of the guards,” where microRNA levels decreased but small transfer RNA fragments (tRFs) increased in post-stroke blood. This molecular switch may re-balance acetylcholine signaling in CD14+ monocytes by regulating their gene expression and modulating post-stroke immunity. Our observations point out to tRFs as molecular regulators of post-stroke immune responses that may be potential therapeutic targets.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73570
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-735707
UR  - https://www.medrxiv.org/content/10.1101/2020.07.02.20144212v2
IS  - 2020.07.02.20144212 Version 2
ER  -