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会分泌一些不同的细胞因子，而且还会接触到一些不同的细胞因子。因此，在炎症的不同阶段，细胞可能暴露在各种不同的细胞因子组合中。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。到目前为止，不同的细胞因子组合对免疫细胞命运的生理相关性在很大程度上被忽视了，但可能构成了免疫反应影响其诱导的反应的特异性的中心机制。免疫应答的失调会导致病原体、组织损伤和自身免疫性疾病的持续存在。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/ST2)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，在靶细胞中，当两个受体都被激活时，与只有一个受体被激活时，在靶细胞中诱导出根本不同的反应。肺泡巨噬细胞高度表达IL-33和EGF受体，而巨噬细胞对清除肺部细菌感染至关重要。因此，我们的发现具有直接的生理学相关性，并可能解释为什么接受EGF-R拮抗剂治疗的癌症患者显示出更高的机会性感染水平，以及许多潜在的解释，为什么联合使用EGF-R拮抗剂和mTOR抑制剂的患者会遭受严重的细菌性肺部感染。在这个项目中，我们将在分子水平上确定两个细胞因子受体的相互作用如何影响在靶细胞中诱导的反应的特异性。为此，我们将利用全球蛋白质组学的方法，剖析一个受体诱导的信号影响另一个受体诱导的信号的分子机制，以及这种相互作用如何影响诱导信号的生理特异性。同时，我们将使用细菌肺部感染的体内模型系统来分析这种相互作用的生理学相关性。这个项目将把蛋白质组学的力量与信号转导的分子生物学分析和肺部感染治疗的体内模型的专业知识结合起来。它将阐述细胞因子释放的组合如何影响免疫反应的特异性，从而打开在治疗环境中有针对性地影响免疫反应的机会。

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.