MicroRNA-155 aggravates ischemia–reperfusion injury by modulation of inflammatory cell recruitment and the respiratory oxidative burst

Abstract

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.

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling

“…This was confirmed by Eisenhardt et al [5], who identified CD11b + myeloid cells as an important source of microRNA-155 in the infarct area. The expression of microRNA-155 in myeloid cells greatly influences cell function.…”

“…In those studies, the knockout of microRNA-155 in LAD-ligated mice improved LV function, reduced infarct size, and attenuated collagen deposition, whereas its overexpression led to the opposite effects [5,10]. MicroRNA-155 knockout also resulted in decreased recruitment of neutrophils and monocytes to the infarct area [5]. …”

“…Transfection of monocyte cultures with microRNA-155 mimic led to increased proinflammatory cytokine and chemokine production and expression of the chemokine receptor CCR7, whereas IL-10 secretion and CCR2 expression were decreased [13,14]. These effects of microRNA-155 in monocytes and macrophages were attributed, at least in part, to a decreased repression of the suppressor of cytokine signaling-1 and SH2-containing inositol-5′-phosphatase 1, potent inhibitors of inflammation [5,6,13]. …”

“…Actively and passively released from cells, they are found in most extracellular fluids of the body [4]. MicroRNA-155, an inflammation-related microRNA [5], is upregulated in activated inflammatory cells and modulates immune responses by regulating cell differentiation (e.g., macrophage polarization), function (e.g., lymphocytes and dendritic cells), and cytokine secretion (e.g., IL-6) [6,7]. Matsumoto et al [8] observed that the serum level of microRNA-155 was 4-fold higher in patients with acute MI who died of cardiac causes within 1 year following hospital discharge.…”

Failed Downregulation of Circulating MicroRNA-155 as a Marker of Adverse Left Ventricular Remodeling: A New Useful Tool for Cardiologists?

“…Eisenhardt et al [6] have reported that mice with a deficiency in miR-155 are relatively protected from ischemia and reperfusion injury, thus suggesting the potential role of miR inhibitors as a new therapeutic approach in tissue protection.…”