Myeloperoxidase‐Derived 2‐Chlorofatty Acids Make Neutrophils Go NETs

Abstract

Neutrophils represent the major effector cells of innate immunity. One mechanism for neutrophil‐mediated microbe killing is through the release of neutrophil extracellular traps (NETs). NET formation (NETosis) involves the fusion of granule and nuclear contents, which are then released in the extracellular space to capture and kill microbes. Chlorinated fatty acids (2‐ClFAs) are a product of neutrophil activation as a result of the myeloperoxidase (MPO) product, HOCl, targeting plasmalogen phospholipids. In this study, we examined the role of 2‐ClFA as an important lipid mediator of NETosis. Treating human peripheral blood neutrophils with physiological levels of 2‐ClFAs led to the formation of NETs, characterized by MPO association with DNA and neutrophil elastase (NE) redistribution to the perinuclear area. NETs induced by 2‐ClFA treatment were as efficient in killing bacteria as those produced by stimulating neutrophils with phorbol myristate acetate (PMA), a potent activator of NETosis. Like PMA, 2‐ClFA‐induced NETosis is calcium‐ and protein arginine deiminase 4 (PAD4)‐dependent. Interestingly, while PMA‐induced NETosis requires neutrophil activation, 2‐ClFAs initiate the NETosis process without neutrophil activation and degranulation. Furthermore, unlike PMA, 2‐ClFA elicits NETosis in bone‐marrow derived neutrophils from MPO deficient mice. Overall, 2‐ClFA may have an important role in directing neutrophil fate following activation, mediating the production on NETs and providing a new pharmacological target to either enhance bacterial killing or reduce host injury during inflammation.Support or Funding InformationThis study was supported by research funding from the National Institute of Health R01 GM‐115553 to D.A.F.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.