Inflammatory disease severity is ameliorated by inhibition of neutrophil-derived MPO that supports endothelial/epithelial integrity

Abstract

Abstract Neutrophils are the most abundant leukocytes and provide a first line of defense against pathogens. Neutrophil granules store enzymes with anti-bacterial activities that can also damage tissues when released in an uncontrolled manner. Neutrophil infiltrates are prevalent in damaged tissues from mice with experimental autoimmune encephalomyelitis (EAE), dextran sodium sulfate (DSS)-colitis and contact hypersensitivity (CHS). The most cytotoxic and abundant enzyme expressed by neutrophils is myeloperoxidase (MPO). MPO utilizes hydrogen peroxide to generate highly reactive molecular moieties, that modify proteins, lipids and DNA, resulting in tissue damage. A pathogenic role for MPO was observed in EAE, DSS-colitis and CHS. MPO-deficiency, is associated with improved functioning of the vasculature, indicating that vasculature is a important target of MPO-activity. However, the precise molecular targets, associated with neutrophil-derived MPO are not known. To establish the importance of MPO as a candidate for therapeutic inhibition, we used animal models of colitis and CHS. Our strategy to modulate MPO activity was the use of MPO-deficient animals and the MPO-specific inhibitor KYC (N-acetyl lysyltyrosylcysteine amide). Our data indicated that MPO-deficient animals, exhibited significantly reduced disease severity in both DSS-colitis and CHS, which correlated with reduced intestinal and vascular permeability, respectively. In addition, MPO inhibition with KYC was also an effective strategy to reduce colitis and CHS severity. KYC mediated MPO inhibition enhanced endothelial integrity in vitro. Our data indicate that MPO could be potential therapeutic target in the treatment of inflammatory diseases.