Eisenhardt Steffen U, Weiss Jakob B W, Smolka Christian, Maxeiner Johanna, Pankratz Franziska, Bemtgen Xavier, Kustermann Max, Thiele Jan R, Schmidt Yvonne, Bjoern Stark G, Moser Martin, Bode Christoph, Grundmann Sebastian
Department of Plastic and Handsurgery, University of Freiburg Medical Center, Freiburg, Germany,
Basic Res Cardiol. 2015 May;110(3):32. doi: 10.1007/s00395-015-0490-9. Epub 2015 Apr 28.
The inflammatory sequelae of ischemia-reperfusion injury (IRI) are a major causal factor of tissue injury in various clinical settings. MicroRNAs (miRs) are short, non-coding RNAs, which regulate protein expression. Here, we investigated the role of miR-155 in IR-related tissue injury. Quantifying microRNA-expression levels in a human muscle tissue after IRI, we found miR-155 expression to be significantly increased and to correlate with the increased expression of TNF-α, IL-1β, CD105, and Caspase3 as well as with leukocyte infiltration. The direct miR-155 target gene SOCS-1 was downregulated. In a mouse model of myocardial infarction, temporary LAD ligation and reperfusion injury resulted in a smaller area of necrosis in miR-155-/- animals compared to wildtype animals. To investigate the underlying mechanisms, we evaluated the effect of miR-155 on inflammatory cell recruitment by intravital microscopy and on the generation of reactive oxygen species (ROS) of macrophages. Our intravital imaging results demonstrated a decreased recruitment of inflammatory cells in miR-155-/- animals during IRI. The generation of ROS in leukocytic cells of miR-155-/- animals was also reduced. RNA silencing of the direct miR-155 target gene SOCS-1 abrogated this effect. In conclusion, miR-155 aggravates the inflammatory response, leukocyte infiltration and tissue damage in IRI via modulation of SOCS-1-dependent generation of ROS. MiR-155 is thus a potential target for the treatment or prevention of IRI.
缺血再灌注损伤（IRI）的炎症后遗症是各种临床环境中组织损伤的主要致病因素。微小RNA（miR）是短的非编码RNA，可调节蛋白质表达。在此，我们研究了miR-155在IR相关组织损伤中的作用。通过量化IRI后人肌肉组织中的微小RNA表达水平，我们发现miR-155表达显著增加，且与TNF-α、IL-1β、CD105和Caspase3的表达增加以及白细胞浸润相关。miR-155的直接靶基因SOCS-1被下调。在心肌梗死小鼠模型中，与野生型动物相比，miR-155基因敲除动物的临时左前降支结扎和再灌注损伤导致坏死面积更小。为了研究潜在机制，我们通过活体显微镜评估了miR-155对炎症细胞募集的影响以及对巨噬细胞活性氧（ROS）生成的影响。我们的活体成像结果表明，在IRI期间，miR-155基因敲除动物中炎症细胞的募集减少。miR-155基因敲除动物白细胞中ROS的生成也减少。miR-155直接靶基因SOCS-1的RNA沉默消除了这种作用。总之，miR-155通过调节SOCS-1依赖的ROS生成加重IRI中的炎症反应、白细胞浸润和组织损伤。因此，miR-155是治疗或预防IRI的潜在靶点。
