Abstract
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.
Highlights
MATERIALS AND METHODSSystemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation, and inflammation in multiple organs [1]
We have shown recently that bradykinins (BK) and captopril [an Angiotensin-converting enzyme (ACE) inhibitor (ACEi)] suppressed Type I IFN responses in murine dendritic cells (DCs) from normal and lupus-prone mice and in human peripheral blood mononuclear cells (PBMC) [13]
We found constitutively increased interferon responsive genes (IRGs) in the brain and kidney of young MRL/lpr mice as compared to the MRL/wt (8-week-old), measured by quantitative PCR (qPCR) (Figure 1A)
Summary
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation, and inflammation in multiple organs [1]. Systemic or oral administration of captopril (starting at 9 weeks of age) effectively reduced Type I IFN responses, peripheral and CNS inflammation revealed by decreased inflammatory cytokines and reduced microglial activation and reduced depressive-like behavior in the MRL/lpr mice. Recombinant IFNα (5 × 105 U/mouse) was administered to MRL/lpr mice via osmotic pumps (Alzet, CA, United States) that were inserted subcutaneously following sterile procedures. Intracellular staining for IFNα was performed after permeabilizing the fixed cells in 1x permeabilizing buffer containing saponin (eBioscience) followed by incubation with purified anti-mouse IFNα antibody (Leinco Technologies, MO, United States) for 1 h at room temperature. For kidney and brain tissues, 150 μl of conjugated IgG antibody (1:50 dilution in Dako diluent; Agilent, CA, United States) was added to each section and incubated overnight at 4◦C. P < 0.05 were considered significant and marked in the figures as follows: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001
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