Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade

Katarzyna Winek, Sebastian Lobentanzer, Bettina Nadorp, Serafima Dubnov, Claudia Dames, Sandra Jagdmann, Gilli Moshitzky, Benjamin Hotter, Christian Meisel, David S. Greenberg, Sagiv Shifman, Jochen Klein, Shani Shenhar-Tsarfaty, Andreas Meisel, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

Abstract

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 downregulation 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.

Original languageEnglish
Pages (from-to)32606-32616
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number51
DOIs
StatePublished - 22 Dec 2020

Keywords

  • Acetylcholine
  • Immunology
  • Ischemic stroke
  • MicroRNA
  • Transfer RNA fragment

Fingerprint

Dive into the research topics of 'Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade'. Together they form a unique fingerprint.

Cite this