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.