Establishment of a mouse model of propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis
摘要Antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis(AAV)is a systemic au-toimmune disease characterized by small-vessel inflammation and the presence of ANCAs,which primarily target myeloperoxidase(MPO)and proteinase 3.Propylthiouracil(PTU),an antithyroid drug,is known as a causative drug of MPO-AAV.PTU induces the forma-tion of DNase I-resistant neutrophil extracellular traps(NETs),which act as autoantigen sources and trigger the production of MPO-ANCAs.Although a rat model of PTU-induced AAV has been established,previous attempts to develop a corresponding mouse model have failed to replicate its histopathological features.In this study,we developed a novel murine model of PTU-induced AAV by enhancing neutrophil recruitment through intra-peritoneal injection of thioglycolate,followed by intraperitoneal administration of phorbol 12-myristate 13-acetate and PTU to induce DNase I-resistant NETs.Freund's complete adjuvant was coadministered intradermally to amplify the immune response.This protocol resulted in abundant NET deposition in peritoneal tissues,elevated MPO-ANCA levels,and the development of pauci-immune glomerular lesions that closely resembled those observed in human AAV.Furthermore,a modified enzyme-linked immunosorbent assay(ELISA)reliably quantified murine MPO-ANCA levels.Thus,we established a novel murine model of PTU-induced AAV that recapitulates both the serological and histopathological features of the human disease.This model provides a valuable platform for investigating disease mechanisms,including NETs-and ANCA-mediated AAV pathogenesis.
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