Peroxynitrite: cellular pathology and implications in autoimmunity

In inflamed tissues, the reaction of nitric oxide and superoxide leads to the formation of an extremely reactive peroxynitrite (ONOO−), which is a well known oxidizing and nitrating agent that exhibits high reactivity at physiological pH. The peroxynitrite formed can attack a wide range of biomolecules via direct oxidative reactions or indirect radical-mediated mechanisms thus triggering cellular responses leading to cell signaling, oxidative injury, committing cells to necrosis or apoptosis. Cellular DNA is an important target for ONOO− attack, and can react with deoxyribose, nucleobases or induces single strand breaks. The free radical-mediated damage to proteins results in the modification of amino acid residues, cross-linking of side chains and fragmentation. Free/protein-bound tyrosines are attacked by various reactive nitrogen species (RNS), including peroxynitrite, to form free/protein-bound nitrotyrosine (NT). The formation of NT represents a specific peroxynitrite-mediated protein modification, and the detection of NT in proteins is considered as a biomarker for endogenous peroxynitrite activity. The peroxynitrite-driven oxidation and nitration of biomolecules may lead to autoimmunity and age-related neurodegenerative diseases. Hence, peroxynitrite modified DNA and nitrated proteins can act as neoantigens and lead to the generation of autoantibodies against self-components in autoimmune disorders.