Myeloperoxidase-dependent tyrosine halogenation potentiates α-defensins functions

Abstract

AbstractNeutrophils are immune cells specialized in detecting and eliminating microbes through potent cytotoxic mechanisms. Most of the neutrophil antimicrobial proteins are stored in intracellular organelles called granules, which are rapidly mobilized to direct the neutrophil cytotoxic machinery against the microbe. However, it remains unclear how the cytotoxic mechanisms cooperate with each other to minimize self-damage and allow an efficient immune response. Here we show that after neutrophil activation, highly oxidative myeloperoxidase-derived hypohalous acids target the antimicrobial peptides α-defensin 1-3, leading to chlorination of tyrosine 21 and iodination of tyrosine 16. We observe α-defensin 1-3 halogenation in rat neutrophils, and notably, in sputum samples from Cystic Fibrosis patients as well as inStreptococcus pneumoniaebronchoalveolar lavage (BAL) andStaphylococcus aureusskin abscesses infected patients. Importantly, halogenated α-defensins are more efficient immunomodulators and anti-toxin mediators than the non-modified peptides, indicating that this rare post-translational modification is important for inflammation.