Tissue kallikrein suppresses interferon responses and reduces depressive-like behavior in lupus-prone mice.

Abstract

Abstract Recent studies show that systemic immune responses, including Type I IFNs, affect neuroinflammation and neuropsychiatric responses. Major depression is the most common psychiatric presentation of NPSLE. Reports indicate that neuropsychiatric symptoms, especially depression and anxiety, may be common co-morbidities of childhood-onset of SLE and clinical studies have demonstrated that IFNα can cause depressive symptoms. The management of patients with neuropsychiatric lupus (NPSLE) continues to be a major therapeutic challenge. We have shown that the kallikrein-kinin system (KKS) [comprised of kallikreins (klks), bradykinins (BKs)] and angiotensin converting enzyme inhibitors (ACEi’s), suppressed Type I IFN responses in murine dendritic cells (DCs) from normal and lupus-prone mice and human peripheral blood mononuclear cells (PBMC). Other studies have shown that klk genes are decreased in lupus patients; giving exogenous klk1 ameliorated kidney pathology in mice. We administered (retro-orbitally) adenovirus carrying the kallikrein gene (klk1- a widely expressed tissue klk) in the MRL/lpr lupus-prone mice (at early disease onset) and analyzed immune responses and depressive-like behavior response. Klk1 improved depressive-like behavior, suppressed Interferon Responsive Genes, decreased splenic plasmacytoid DCs, and reduced plasma IFNa levels. Together, these findings suggest that kallikreins and other KKS molecules may be used to control IFNa production/responses and other inflammatory responses in SLE and NPSLE. This work was supported by NIH Grant R21AR071679 and funds from the Department of Pathology and Laboratory Medicine.