Establishment of a mouse model of propylthiouracil‐induced antineutrophil cytoplasmic antibody‐associated vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune 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 formation 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 intraperitoneal 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.