N-chlorination mediates protective and immunomodulatory effects of oxidized human plasma proteins

Hypochlorous acid (HOCl), a powerful bactericidal and fungicidal oxidant, is produced by neutrophils to fight infections. To prevent tissue damage at sites of inflammation, excess HOCl is scavenged by serum albumin and other plasma proteins. Here we show that plasma proteins are not only an effective sink for HOCl, but that HOCl-induced N-chlorination converts plasma proteins into chaperone-like holdases that protect other proteins from aggregation. This chaperone-like conversion was reversible by antioxidants and was abrogated by prior methylation of basic amino acids. Furthermore, reversible N-chlorination of basic amino acid side chains is the major factor that converts plasma proteins into efficient activators of immune cells. Finally, HOCl-modified serum albumin was found to act as a pro-survival molecule that protects neutrophils from cell death induced by highly immunogenic foreign antigens. We propose that activation and enhanced persistence of neutrophils mediated by HOCl-modified plasma proteins, resulting in the increased and prolonged generation of ROS, including HOCl, constitutes a potentially detrimental positive feedback loop that can only be attenuated through the reversible nature of the modification involved.