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

Wiley - Tập 64 Số 11 - Trang 3779-3787 - 2012
Daigo Nakazawa1, Utano Tomaru1, Akira Suzuki2, Sakiko Masuda1, Risa Hasegawa1, Toshiaki Kobayashi1, Saori Nishio1, Masanori Kasahara1, Akihiro Ishizu3
1Hokkaido Univ., Sapporo, Japan
2KKR Sapporo Medical Center, Sapporo, Japan
3Hokkaido University, Sapporo, Japan

Tóm tắt

AbstractObjectiveNeutrophil 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.MethodsNETs 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.ResultsWhen 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.ConclusionOur 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.

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Wiley

Tập 64 Số 11

3779-3787

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