Dissecting the interaction between the EGF-R and IL33-R signalling pathway and its physiological relevance for resistance against bacterial lung infec

在炎症期间，免疫系统的细胞不仅分泌许多不同的细胞因子，而且还暴露于许多不同的细胞因子。在炎症的不同阶段，细胞可以暴露于各种不同的细胞因子组合。因此，每个细胞都必须整合各种外部信号，以确保正确的细胞命运决定。迄今为止，细胞因子的不同组合对免疫细胞命运的生理相关性在很大程度上被忽视，但可能构成免疫应答可以影响其诱导的应答的特异性的中心机制。免疫反应的失调可导致病原体的持续存在、组织损伤和自身免疫性疾病，我们发现两种细胞因子受体，表皮生长因子受体（EGF-R）和白细胞介素-33受体（T1/ST 2），在物理上相互作用，并能够影响另一种受体诱导的生理反应。因此，当两种受体都被激活时，与仅其中一种受体被激活时相比，在靶细胞中诱导了根本不同的反应。肺泡巨噬细胞高度表达IL-33受体和EGF受体，这对于清除细菌性肺部感染至关重要。因此，我们的发现具有直接的生理相关性，并且可能潜在地解释为什么用EGF-R拮抗剂治疗的癌症患者显示出增强的机会性感染水平，并且许多潜在地解释为什么用EGF-R拮抗剂以及用mTOR抑制剂共同治疗的患者可能遭受严重的细菌性肺部感染。我们将确定在分子水平上两种细胞因子受体的相互作用如何影响靶细胞中诱导的应答的特异性。为此，使用全球蛋白质组学的方法，我们将剖析的分子机制，其中一个受体诱导的信号影响由其他受体诱导的信号，以及这种相互作用如何影响诱导信号的生理特异性。与此同时，我们将分析这种相互作用的生理相关性，使用细菌肺部感染的体内模型系统。总之，这个项目将联合收割机结合蛋白质组学的优势与信号转导的分子生物学分析的专业知识和肺部感染的治疗性治疗的体内模型。它将解决细胞因子释放的组合如何影响免疫应答的特异性，从而将打开在治疗环境中靶向影响免疫应答的机会。

During inflammation cells of the immune system not only secrete a number of different cytokines but are also exposed to a number of different cytokines. Under different stages of inflammation, cells could thereby be exposed to a wide variety of different combinations of cytokines. Therefore each cell has to integrate a variety of external signals to ensure proper cell-fate decisions. The physiological relevance of different combinations of cytokines on the fate of immune cells has largely been overlooked so far, but may constitute a central mechanism by which an immune response can influence the specificity of the response it induces. Disregulation of immune responses can lead to the persistence of pathogens, tissue damage and auto-immune diseases.We have found that two cytokine receptors, the Epidermal Growth Factor Receptor (EGF-R) and the Interleukin-33 Receptor (T1/ST2), physically interact with each other and are able to influence the physiological responses that the other receptor induces. As a result, fundamentally different responses are induced in target cells when both receptors are activated compared to when only one of them is activated. Both the IL-33- and EGF-receptors are highly expressed by aveolar macrophages, which are crucial for the clearance of bacterial lung infections. Therefore, our findings have direct physiological relevance and may potentially explain why cancer patients treated with EGF-R antagonists show an enhanced level of opportunistic infections, and many potentially explain why patients co-treated with EGF-R antagonists as well as with mTOR inhibitors can suffer of severe bacterial lung infections.In this project, we will determine how on a molecular level the interaction of two cytokine receptors influence the specificity of the response induced in target cells. To this end, using a global proteomics approach, we will dissect the molecular mechanism by which a signal induced by one receptor influences the signal induced by the other receptor and how this interaction influences the physiological specificity of the induced signals. In parallel will we analyse the physiological relevance of this interaction, using in vivo model systems of bacterial lung infections.Taken together, this project will combine the strength of proteomics with the expertise of molecular biological analysis of signal transduction and in vivo models of the therapeutic treatment of lung infections. It will address how the combination of cytokine release influence the specificity of immune responses and thus will open the opportunity to targeted influence immune responses in a therapeutic setting.