Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi's may have potential for therapeutic use for systemic and NPSLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Interferon- α (IFN-α) is a central mediator in disease pathogenesis. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE often causing depression. Administration of IFN-α in patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation and brain functions. It is known that ACE degrades bradykinin into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells that the effects of captopril (an ACE inhibitor) on IFN responsive gene inhibition were reversed when bradykinin receptors were blocked, suggesting that ACE, in part, acts via kinin receptors to bring about the suppressive effects. We used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to check the in vivo effects of captopril on IFN-induced immune responses, neuroinflammation, and behavior. Exposing MRL/lpr mice to IFN-α increased depressive-like behavior and enhanced ACE expression in the brain. Administering captopril in MRL/lpr mice decreased expression of IFN responsive genes in brain and kidney, decreased microglial activation (IBA1 expression) and reduced depressive-like behavior as assessed by the forced swim test. Thus, ACE inhibitors may have potential for therapeutic use for systemic and neurolupus.