Potential of tissue kallikreins as therapeutic targets for neuropsychiatric lupus

组织激肽释放酶作为神经精神性狼疮治疗靶点的潜力 项目总结： 神经精神性狼疮(NPSLE)是人类SLE最常见的表现之一。非系统性红斑狼疮的症状 包括在狼疮确诊后一年内出现的焦虑、抑郁和认知障碍。干扰素(a I型干扰素)，用于某些疾病的治疗，会导致抑郁症状的发展。我们有 激肽释放酶-激肽系统(KKS)[包括激肽释放酶(KLK)、缓激肽(BKS)]和血管紧张素 转化酶抑制剂(ACEI)抑制小鼠树突状细胞(DC)I型干扰素反应 正常和狼疮易感小鼠和人外周血单核细胞(PBMC)。这一现象产生了 非常重要，因为干扰素在狼疮发病机制中起着中心作用。KKS不仅规定了许多经典 过程，如凝血、血管生成和血压控制，但也包括炎症和 大脑功能的调节。血管紧张素转换酶能将BK降解为无活性的多肽，而ACEI有助于恢复BK水平，即 进而抑制干扰素的反应。Klks将激肽原分解为BKS，增加BK水平。利用水井- 建立MRL/LPR和NZBW/F1狼疮易感小鼠模型，我们发现短期口服给药 卡托普利[一种跨越血脑屏障(BBB)的中枢作用的CA-ACEI]降低了干扰素反应基因 (IRGS)在脑、脾和肾，减少神经炎症，改善抑郁样和焦虑样 行为。有趣的是，在MRL/LPR小鼠中使用KLK1(一种广泛表达的组织KLK)也得到了改善 抑郁样行为，抑制IRG，减少脾的浆细胞样树突状细胞，降低血浆干扰素 级别。其他研究表明，在狼疮患者中KLK基因减少；提供外源性KLK1 改善小鼠肾脏病理改变。总之，这些发现表明KKS分子可能被用来 控制系统性红斑狼疮和非系统性红斑狼疮患者干扰素的产生/反应和其他炎症反应。这项建议 目的是调查：(1)KLK1对全身性和非系统性红斑狼疮疾病结局的影响(临床，病理， 免疫学和行为学)在自发的MRL/LPR小鼠模型(2)免疫调节作用 狼疮易感小鼠(MRL/LPR和SLE 1，2，3)和野生型(MRL/wt，B6)小鼠脑细胞中KLK1的表达。由此得出的结论 该提案将为KLK分子治疗系统性红斑狼疮和NPSLE提供理论依据。

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.