Title: Potential of tissue kallikreins as therapeutic targets for neuropsychiatric lupus Project summary: Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE. Symptoms in NPSLE include anxiety, depression and cognitive impairment that present within one year of lupus diagnosis. IFN (a Type I IFN), used as a therapeutic in certain diseases, causes development of depressive symptoms. 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). This phenomenon has immense importance, as IFN is a central player in lupus pathogenesis. The KKS not only regulates many classic processes, such as coagulation, angiogenesis, and control of blood pressure, but also inflammation and regulation of brain functions. ACE degrades BK to inactive peptides, while ACEi’s help to restore BK levels, that in turn suppress IFN responses. Klks breakdown kininogens to BKs, increasing BK levels. Using the well- established MRL/lpr and NZBW/F1 lupus-prone mouse models, we showed that short-term oral administration of captopril [a blood-brain barrier- (BBB) crossing, centrally acting CA-ACEi] decreased IFN responsive genes (IRGs) in brain, spleen and kidney, decreased neuroinflammation, and improved depressive-like and anxiety-like behavior. Interestingly, administration of klk1 (a widely expressed tissue klk) in MRL/lpr mice also improved depressive-like behavior, suppressed IRGs, decreased splenic plasmacytoid DCs, and reduced plasma IFN levels. Other studies have shown that klk genes are decreased in lupus patients; giving exogenous klk1 ameliorated kidney pathology in mice. Together, these findings suggest that KKS molecules may be used to control IFN production/responses and other inflammatory responses in SLE and NPSLE. The proposal aims are to investigate: (1) effects of klk1 on systemic and NPSLE disease outcomes (clinical, pathological, immunological and behavioral) in the spontaneous MRL/lpr mouse model (2) the immunomodulatory effects of klk1 in brain cells of lupus prone (MRL/lpr and Sle 1,2,3) and wild type (MRL/wt, B6) mice. Findings from this proposal will provide a rationale for therapeutic use of klk molecules for systemic lupus and NPSLE.