Mechanisms of mast cell activation and function in natural immunity 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。利用MC基因缺陷的KitW/KitW-v小鼠，我们和其他人已经证明，MC的激活，即由补体成分激活，对于盲肠结扎和穿孔(CLP)诱导的急性感染性腹膜炎建立保护性宿主防御是必不可少的，部分原因是MC招募具有杀菌特性的循环白细胞。然而，在很大程度上还不清楚1)MC是如何被激活的，2)MC如何在先天性免疫反应的背景下提供对宿主的保护。内皮素-1(ET-1)是一种强大的血管收缩和MC促分泌剂，与感染性腹膜炎的发病率和死亡率密切相关，并且在CLP后，KitW/KitW-v-小鼠腹膜中ET-1水平显著升高。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，我们将结合使用来自ETA-/-和ETB-/-胚胎干细胞的ET-1受体缺陷MC的遗传学方法，涉及KitW/KitW-v-小鼠和MC敲入小鼠的过继移植技术，以及高度相关的活体模型，包括CLP。保护性自然免疫反应可以通过上调MC数量和/或功能来增强。我们的研究可能通过识别MC激活和/或细菌天然免疫反应中的效应器功能的新的潜在机制来扩展这一潜在的治疗策略。

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.