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-? 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-? in chronic viral infections and cancer causes depression-like symptoms in a high percentage of patients. Genetically determined upregulated levels of IFN-? 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.
This R21 proposal aims to (1) analyze the effects of the kallikrein-kinin system (KKS) and mechanisms involved in regulating Type I Interferon responses in immune subsets in mice and humans and (2) study the impact of captopril, an ACE inhibitor, and bradykinins on disease outcome in systemic and neurolupus and provide insights into new therapeutic targets.
