Myeloperoxidase (MPO) is known to locally contribute to organ damage in various chronic inflammatory conditions by generating reactive intermediates, which makes it an attractive potential therapeutic target. The contribution of MPO in the development of experimental lupus is unknown. The aim of these studies was to define the role of MPO in murine lupus nephritis.
Lupus nephritis was induced in C57BL/6 wildtype 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 wildtype and Mpo-/- mice were assessed 3 or 6 days after pristane injection.
Mpo-/- mice developed more severe nephritis than wildtype mice, despite having reduced circulating levels of autoantibodies and glomerular deposition of IgG and complement, as well as 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 was, in turn, 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 pristane-induced early cell apoptosis, leukocyte accumulation and pro-inflammatory cytokine expression in the peritoneum.
Overall, MPO attenuates pristane-induced lupus nephritis by inhibiting early inflammatory responses in the peritoneum and limiting the generation of CD4 T cell autoimmunity in secondary lymphoid organs, despite increasing levels of oxidative stress and local deposition of humoral mediators of injury. This immunosuppressive function of MPO, which overrides its injurious effects in the kidney, should be considered when designing MPO-specific therapies for the treatment of inflammatory diseases.