Suppression of autoimmunity and renal disease in pristane-induced lupus by myeloperoxidase

Dragana Odobasic, Ruth Cecilia Magdalene Muljadi, Kim O'Sullivan, Anthony James Kettle, Nina Dickerhof, Shaun Andrew Summers, Arthur Richard Kitching, Stephen Roger Holdsworth

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17 Citations (Scopus)

Abstract

OBJECTIVE: Myeloperoxidase (MPO) locally contributes to organ damage in various chronic inflammatory conditions by generating reactive intermediates. The contribution of MPO in the development of experimental lupus is unknown. The aim of this study was to define the role of MPO in murine lupus nephritis (LN). METHODS: LN was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO(-/-) ) mice by intraperitoneal injection of pristane. Autoimmunity and glomerulonephritis were assessed 20 and 40 weeks after pristane administration. Cell apoptosis, leukocyte accumulation, and cytokine levels in the peritoneal cavity of WT and MPO(-/-) mice were assessed 3 or 6 days after pristane injection. RESULTS: MPO(-/-) mice developed more severe nephritis than did WT mice 20 and 40 weeks after pristane injection, despite having reduced glomerular deposition of antibody and complement and diminished levels of markers of oxidative stress (oxidized DNA and glutathione sulfonamide). Enhancement of renal disease in MPO-deficient mice correlated with increased accumulation of CD4+ T cells and macrophages in glomeruli, which, in turn, was associated with augmented generation of CD4+ T cell responses and increased activation and migration of dendritic cells in secondary lymphoid organs. In addition, the enhanced renal injury in MPO(-/-) mice was associated with increased glomerular accumulation of neutrophils and deposition of neutrophil extracellular traps. MPO deficiency also increased early cell apoptosis, leukocyte accumulation, and proinflammatory cytokine expression in the peritoneum. CONCLUSION: MPO attenuates pristane-induced LN by inhibiting early inflammatory responses in the peritoneum and limiting the generation of CD4+ T cell autoimmunity in secondary lymphoid organs.
Original languageEnglish
Pages (from-to)1868 - 1880
Number of pages13
JournalArthritis and Rheumatology
Volume67
Issue number7
DOIs
Publication statusPublished - 2015

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