Stroke is a global burden, accounting for ∼5.5 million deaths each year, and leaving most of the survivors permanently disabled. The immune system is one of the main participants in the pathophysiology of stroke. Brain injury can inhibit immune functions in the periphery, which limits the inflammatory response and infiltration of immune cells into the central nervous system (CNS) and may form a neuroprotective mechanism in stroke patients. However, this systemic immunosuppression also increases the risk of infectious complications, for example, by inducing lymphocyte apoptosis and reducing the production of proinflammatory cytokines such as monocytic TNF-α and lymphocytic IFN-γ. Thus, poststroke recovery depends largely on a delicate balance between inflammation, which exacerbates the severity of symptoms, and the poststroke suppression of immune functions, which increases susceptibility to infections.
Recently, microRNAs (miRs) have attracted more and more interest from researchers, mainly because they have a wide range of regulatory functions. To examine these functions of stroke, Lobentanzer joined Katarzyna Winek of Hebrew University, Jerusalem, to study microRNA and tRNA fragments in blood samples from ischemic stroke patients collected from Charité, Berlin. " Transfer RNA fragments (tRFs) have until now been thought to be fragments of RNA transporters and have recently been shown to have biological functions; naturally, we are very interested in that," Lobentanzer explained. The related results were published in the international journal PNAS.
Both miRs and tRFs may control the whole biological pathways, so their balanced orchestration could modulate brain-induced systemic immune functioning. Recent reports emphasize tRNA as a major source of small-noncoding RNA, including tRNA halves (tiRNAs) and smaller tRFs. tiRNAs are produced by angiogenin cleavage at the anticodon loop, which increases the possibility that the poststroke angiogenin increase might change their levels. Among other functions, smaller fragments derived from the 3’-tRF/5’-tRF or internal tRNA parts (i-tRF) may incorporate into Argonaute (Ago) protein complexes and suppress their targets like miRs. Differential expression of tRFs was reported under ischemic reperfusion, hypoxia, oxidative stress, and in epilepsy, which are all related to ischemic stroke complications.
Figure 1. Immune cell tRF expression clustering and cell type-specific analysis. (Winek K, et al., 2020)
In this study, researchers performed small and long RNA sequencing (RNA-seq) of whole-blood samples collected from ischemic stroke patients 2 days after stroke onset, and mined RNA-seq datasets of blood cell transcripts. They found a stroke-induced decline of miRs and concomitant elevation of tRFs in whole blood, and demonstrated that this shift may be related to the poststroke cholinergic blockade of immune function. Mining transcriptomic datasets identified CD14+ monocytes as likely pivotal in the cholinergic control of immunity, which indicated that the stroke-induced tRFs may target specific monocytic TFs, and at least some of those tRFs may actively control processes linked to inflammatory responses. In addition, the overexpression of tRF-22-WE8SPOX52 using ssRNA mimics resulted in the down-regulation of its Zbp1 target, which is involved in regulating inflammatory responses. The concept of integrated fine-tuning of poststroke immune responses opens a new field for stroke diagnostics and therapeutics.