Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis.
OBJECTIVE
Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV.


METHODS
NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats.


RESULTS
When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum.


CONCLUSIONS
Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.
Hokkaido University, Sapporo, Japan.
Daigo
D
Nakazawa
Utano
U
Tomaru
Akira
A
Suzuki
Sakiko
S
Masuda
Risa
R
Hasegawa
Toshiaki
T
Kobayashi
Saori
S
Nishio
Masanori
M
Kasahara
Akihiro
A
Ishizu
D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D000963:Antimetabolites / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D004247:DNA / Q000276:immunology / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009195:Peroxidase / Q000276:immunology* / Q000378:metabolism; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D023084:alpha-Defensins / Q000276:immunology / Q000378:metabolism
D000963:Antimetabolites; D002273:Carcinogens; D023084:alpha-Defensins; D011441:Propylthiouracil; D004247:DNA; D009195:Peroxidase; D003850:Deoxyribonuclease I; D013755:Tetradecanoylphorbol Acetate