Mechanisms of mast cell activation and function in natural immunity to bacteria

肥大细胞激活机制及其在细菌自然免疫中的功能

• 批准号: 5357782
• 负责人: Professor Dr. Marcus Maurer
• 金额: --
• 依托单位: Institut für Allergieforschung (IFA)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5357782?language=en
• 关键词: Mechanisms; mast; cell; activation; function

Recent studies indicate that mast cells (MCs), key contributors to the pathology and mortality associated with anaphylaxis and other allergic disorders, can also promote health by participating in natural immune responses to bacterial infections. Using genetically MC-deficient KitW/KitW-v-mice, we and others have shown that the activation of MCs, i.e. by complement components, is essential for mounting protective host defence in acute septic peritonitis induced by cecal ligation and puncture (CLP), in part because MCs recruit circulating leukocytes with bactericidal properties. Yet, it remains largely unclear 1) how MCs are activated and 2) how MCs provide protection of the host in the context of innate immune responses. Endothelin-1 (ET-1), a potent vasoconstrictor and MC secretagogue, contributes significantly to morbidity and mortality of septic peritonitis and ET-1 levels in the peritoneum are greatly increased in KitW/ KitW-v-mice after CLP. We hypothesize that 1) ET-1 activates MCs and that 2) MCs regulate ET-1 levels and toxicity at sites of bacterial infection by facilitating degradation, binding, and/or clearance of ET-1. To test these hypotheses, we will combine genetic approaches using ET-1 receptor deficient MCs, derived from ETA-/- and ETB-/- embryonic stem cells, adoptive transfer techniques, involving KitW/KitW-v-mice and "MC knock-in mice", and highly relevant in vivo models, including CLP. Protective natural immune responses can be enhanced by upregulating MC numbers and/or function. Our studies may extend this potential therapeutic strategy by identifying novel underlying mechanisms of MC activation and/or effector functions in innate immune responses to bacteria.

最近的研究表明，肥大细胞（MC），与过敏反应和其他过敏性疾病相关的病理和死亡率的关键贡献者，也可以通过参与对细菌感染的自然免疫反应来促进健康。使用遗传MC缺陷型KitW/KitW-v-小鼠，我们和其他人已经表明，MC的激活，即补体成分，对于盲肠结扎和穿刺（CLP）诱导的急性脓毒性腹膜炎中的保护性宿主防御至关重要，部分原因是MC招募具有杀菌特性的循环白细胞。然而，目前尚不清楚1）MC如何被激活以及2）MC如何在先天免疫反应的背景下提供对宿主的保护。内皮素-1（ET-1）是一种强有力的血管收缩剂和MC促分泌剂，与脓毒性腹膜炎的发病率和死亡率密切相关。我们假设1）ET-1激活MC，2）MC通过促进ET-1的降解、结合和/或清除来调节细菌感染部位的ET-1水平和毒性。为了验证这些假设，我们将联合收割机遗传学方法与高度相关的体内模型（包括CLP）相结合，这些遗传学方法使用来自ETA-/-和ETB-/-胚胎干细胞的ET-1受体缺陷MC、过继转移技术（包括KitW/KitW-v-小鼠和“MC敲入小鼠”）。保护性天然免疫应答可以通过上调MC数量和/或功能来增强。我们的研究可能会扩展这种潜在的治疗策略，通过确定新的潜在机制MC激活和/或效应器功能的先天性免疫反应细菌。