Title: Kallikrein-kinin system and Type I Interferons in systemic and neurolupus
Project Summary:
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage,
frequently involving the skin, kidney, and brain. Type I interferon (IFN) signature is a hallmark of lupus disease.
We have shown that myeloid dendritic cells (DCs) from the Sle 1,2,3 (Sle) lupus-prone mouse model show a
Type I IFN signature that preceeds disease onset. We recently discovered that myeloid DCs from young pre-
diseased lupus-prone Sle mice exhibit remarkably decreased expression of genes from the kallikrein (klk)
family compared to DCs from age-matched wild type C57BL/6 control mice, both in vitro and in vivo. The klk
family of genes is part of the kallikrein-kinin system (KKS), which consists of bradykinins (BK), angiotensin
converting enzyme (ACE), and additional molecules classically involved in important physiological processes
including coagulation, angiogenesis, and control of blood pressure. We further discovered that molecules of
the KKS actually suppressed Type I IFN induced responses in DCs in vitro and spleen and kidney in vivo. Our
discovery of this unanticipated relationship between the KKS and Type I IFN responsive genes (IRGs)
suggests that KKS molecules may be used to control IFN-a production/responses in SLE. Neuropsychiatric
lupus (NPSLE) is one of the most common manifestations of human SLE, causing depression in many. It is
well established that administration of IFN-a in chronic viral infections and cancer causes depression-like
symptoms in a high percentage of patients. Genetically determined upregulated levels of IFN-a have been
found in the brain of lupus-prone mice and have been linked to their anxiety-like behavior. While current
treatment strategies to block IFN in lupus focus only on systemic responses, the role of IFN blockade in
neurolupus has never been studied. Our pilot studies of administering captopril (ACE inhibitor and FDA-
approved drug to treat kidney disease) in MRL (Murphy Roths Large) lupus-prone mice led to decreased
inflammation in the brain and IFN response in the kidney. It is known that ACE decreases BK levels. Our
preliminary findings that BK can suppress IFN responses in mice and humans provide a rationale to investigate
if captopril can also reduce neuroinflammation by decreasing IFN production or responses in the brain, via
increasing BK or other alternate pathways. The studies will reveal if these commonly used drugs can be
“repurposed” for treating neurolupus. We aim to test (1) the effects of putative candidates of the KKS,
specifically on Type I IFN signaling, and analyze the mechanistic pathways of IFN regulation by KKS in DCs
and other immune subsets in mice and normal human subjects, and (2) if captopril and BK can ameliorate
lupus disease (systemic and neurolupus) in murine models.