Shields Up—Systemic Protection Provided by microRNA-21 During Sepsis?*

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Sepsis remains a leading cause of death worldwide. Early initiation of appropriate antimicrobial therapy, as well as advances in intensive care, has reduced early mortality, but mortality rates remain as high as 20–50%, particularly later in the clinical course (1). Much of this mortality is thought to be due to immunodysfunction (2). This has led to the exploration of approaches to modulate the infection-induced inflammatory response in patients, which have had limited success to date. Ischemia-reperfusion (I/R) is a well-described stress response which is triggered when circulation returns to target tissues after a period of restricted blood flow which resulted in anoxic or hypoxic conditions (3). Although the subsequent oxidative stress response can be detrimental in certain contexts such as posttransplant or during cardiac surgery because of tissue injury and necrosis, it has been noted that short, transient episodes of ischemia followed by reperfusion, termed “ischemic preconditioning” (IPC) can be beneficial (4) and has been employed during certain surgeries, such as aortic cross-clamping. An important observation regarding IPC is the finding that induction of ischemia in one organ results in protection in distal organs, suggesting a systemic protective effect induced by I/R (5). Understanding the mechanism underlying the remote protection of IPC offers the possibility of protecting patients with sepsis from the associated tissue damage and progression of multiple organ failure.
Attempts to define the molecular agents which confer systemic protection are ongoing. If these agents are identified, they offer the benefits of IPC, without the deleterious organ-specific side effects. They may also be able to modulate the course of systemic organ failure due to sepsis when given at a clinically feasible time point. Autocrine protein agents like hormones and cytokines have been considered, but a recent article from Jia et al (6) demonstrates that protection by remote IPC is induced by the transfer of exosomes. These cell-derived, membrane-enclosed vesicles (7) leave the target tissue and affect distal organs by transferring RNA contents which modulate gene expression and promote protection. Notably, they find that one small noncoding microRNA (miRNA), miR-21, is key in inducing protection against both endotoxin-induced and cecal ligation and puncture (CLP)-induced sepsis (6). This is important as it does not just identify a new class of biomolecule and method of transport as a means of inducing systemic responses—miRNAs in exosomes, but also because this particular miRNA, miR-21, has been shown to be highly expressed in multiple tissues and dysregulated in many diseases including cancer, inflammatory conditions, and fibrotic disease, although its exact role in pathogenesis is less clear (8–10).
Since miR-21 was reported to control cellular growth and proliferation in a variety of human cancers and has emerged as a bona fide “onco-miR,” silencing of which can promote apoptotic cell death (11, 12), and because of the importance of cell death and proliferation in I/R injury, it stands to reason that this miRNA could regulate the I/R response. Previously, various groups demonstrated that miR-21 was one of the most significantly up-regulated miRNAs induced after I/R injury in kidneys (13, 14) and in the heart (15). This occurs after activation of the hypoxia-sensitive transcription factor hypoxia-induced factor (HIF)-1α in renal epithelia cells (16). Identifying its exact function however, is more complex, compounded by the multitude of potential messenger RNA targets miR-21 can repress in various cell-types. It has been linked to the proliferative response during tissue repair (13). The interpretation of miR-21’s function in the I/R response is complicated by the finding that it may regulate this response in a context- and model-dependent manner.

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