106 - ROS Ameriolates the Clinical Course of Murine Lupus

Abstract

The production of reactive oxygen species (ROS) via the oxidative burst has in the traditional view been connected with promotion of inflammation and tissue damage, but has in recent years also been implicated in regulation of inflammation and protection from autoimmunity. We have investigated the effects of ROS on the autoimmunity in a mouse model of lupus and in patients with systemic lupus erythematosus (SLE). Aims The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity in wild type and Ncf1** mice which carry a point mutation in one of the subunits of the phagocyte NADPH oxidase 2 complex that abrogates ROS-production. Lupus was induced by intraperitoneal injection of 0.5 ml pristane oil and the clinical course was compared by analysis of serological markers and organ involvement. Ex vivo phagocytosis assays and flow cytometry were deployed to assess uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. Potential activators of ROS production were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. Results Our results show that the absence of ROS in Ncf1** mice gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment of pristane-induced lupus with NOX2 agonists ameliorated the clinical course in BALB/c mice, while application of a ROS scavenger worsened disease outcome. Further, downstream nrf2 signalling was decreased in Ncf1** mice. Patients with SLE showed similar aberrant phagocytosis as in murine lupus, and were characterized by higher spontaneous formation of NETs. A fine-tuned balance of ROS-production is necessary to prevent autoimmunity and to avert the development of lupus in mice and men.