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（MCS），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因素也可以通过参与对细菌感染的自然免疫反应来促进健康。我们和其他人使用遗传上的MC缺陷kitw/kitw-v-V-c，表明，MC的激活，即通过补体组件，对于在Cecal结扎和穿刺（CLP）引起的急性化粪池腹膜炎的保护性宿主防御（CLP）中至关重要，因为MCS在MCS proctuit computity computity propersity proport proports properties properties properties properies properies properies properies properies properies properies properies properies properies properies proporties cytiriesicalicic properies。但是，这在很大程度上不清楚1）如何激活MC，以及2）MC在先天免疫反应的背景下如何提供宿主的保护。内皮素-1（ET-1）是一种有效的血管收缩剂和MC促分泌物，在CLP后KITW/ KITW-V-V-小鼠中大大增加了腹膜脓肿的发病率和死亡率。我们假设1）ET-1激活MC，并且2）MCS通过促进ET-1的降解，结合和/或清除率来调节细菌感染部位的ET-1水平和毒性。为了检验这些假设，我们将使用ETA受体缺陷的MC结合遗传方法，这些MC源自ETA - / - 和ETB-/ - 胚胎干细胞，涉及KITW/KITW-V-V-V-V-MICE和“ MC敲击小鼠”的收养转移技术，以及包括CLP在内的Vivo模型，包括CLP。可以通过上调MC数量和/或功能来增强保护性的自然免疫反应。我们的研究可以通过鉴定MC激活和/或效应子功能在对细菌的免疫反应中的新型潜在的基础机制来扩展这种潜在的治疗策略。