Reduction of cPLA_2α overexpression: An efficient anti-inflammatory therapy for collagen-induced arthritis

Cytosolic phospholipase A_2α (cPLA₂) plays an important role in the development of several inflammatory diseases. The aim of the present study is to determine whether inhibition of cPLA₂ expression, using specific antisense oligonucleotides against cPLA₂ (antisense), is efficient in reducing inflammation after its development. Two mouse models of inflammation were included in the study: thioglicolate peritonitis and collagen-induced arthritis (CIA). The antisense was found to be specific and efficient in inhibiting cPLA₂ expression and NADPH oxidase activity ex vivo in peritoneal phagocytes. Immunoblotting and immunohistochemistry analysis showed a significant elevation in cPLA₂ expression in the inflamed joints of collagen-induced arthritis mice localized in cell infiltrate, chondrocytes and the surrounding skin and skeletal muscle. Similarly, the cPLA₂ metabolite, leukotriene B₄, accumulated in the peritoneal cavity of mice with peritonitis. Inhibition of elevated cPLA₂ expression after development of inflammation by intravenous administration of antisense resulted in a dramatic reduction in inflammation and a significant reduction in neutrophils recruitment to the site of inflammation in both mouse models of inflammation. Our results demonstrate the critical role of cPLA₂ for the duration of inflammation and suggest that inhibition of cPLA₂ expression by antisense oligonucleotides may serve as an efficient treatment of inflammatory diseases.