Unravelling the role of AHR signaling in microbe-host interaction in the skin

揭示 AHR 信号在皮肤微生物与宿主相互作用中的作用

• 批准号: 511917392
• 负责人: Professor Dr. Bernhard Homey
• 金额: --
• 依托单位: Hautklinik
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511917392?language=en
• 关键词: Unravelling; role; AHR; signaling; microbe

Recent findings indicate that human health is ‘multiorganismal’. Interactions between commensal or pathogenic microbes and the hosts they colonize are central to the maintenance of homeostasis and the initiation of disease. Detailed knowledge on the skin microbiome and its alterations in a variety of skin diseases is now available. However, specific interactions between microbes and skin cells of the host, including avenues of inter-organismal cell-to-cell communication are less well understood. Recently, it became apparent that a well-known communication receptor, namely the aryl hydrocarbon receptor (AHR) plays a critical role in microbe-host interactions within the gut. The AHR acts as a key sensor of metabolites produced and released by the intestinal microbiota, where they are implicated in the regulation of the mucosal immune system and intestinal barrier function. In particular, the AHR is involved in the binding of microbial-derived metabolites of the essential amino acid L-tryptophan (L-Trp). Although various members of the gut microbiome have now been shown to be involved in pathways that yield biologically active derivatives of L-Trp activating the AHR, the situation in the skin remains largely elusive. In project 1, we aim to generate evidence supporting the role for AHR signaling as a key player in microbe-host interactions maintaining cutaneous homeostasis and when perturbed, facilitating chronic skin inflammation. We are investigating healthy skin and distinct chronic inflammatory skin diseases, such as atopic dermatitis and psoriasis, which have been shown to depend on AHR signaling. The applicant will mine datasets from the unique physical biomaterial collection of project 1 and combine these with recently available public datasets (incl. single cell RNA-Seq data) as well as newly generated transcriptome and microbiome analyses. Here, the applicant will build on these multi-omics datasets to investigate the following specific aims: (1) Unravel the microbe-driven dynamics of Trp-catabolism-dependent cutaneous AHR signaling during homeostasis and chronic skin inflammation. (2) Define functional consequences in keratinocytes, sensory neurons and Schwann cells as cellular targets for AHR ligands to mediate microbe-host interactions in vitro. (3) Validate the modulation of cutaneous homeostasis and chronic skin inflammation through microbe-induced AHR signaling in mice and man in vivo. Findings of the proposed study may shed light into the role of AHR signaling in the interaction pathways between microbes and the host. It may identify important ‘beneficial’ vs. ‘harmful’ microbes as well as their products and define novel strategies based on AHR targeting, which help to maintain cutaneous homeostasis and therapeutically modulate skin inflammation.

最近的研究结果表明，人类健康是“多生物体”的。肠道微生物或病原微生物与它们所定殖的宿主之间的相互作用对于维持体内平衡和疾病的发生至关重要。关于皮肤微生物组及其在各种皮肤疾病中的变化的详细知识现在是可用的。然而，微生物和宿主皮肤细胞之间的特定相互作用，包括生物体间细胞间通讯的途径，还不太清楚。最近，一种众所周知的通讯受体，即芳香烃受体（AHR）在肠道内微生物-宿主相互作用中起着关键作用。AHR充当由肠道微生物群产生和释放的代谢物的关键传感器，其中它们涉及粘膜免疫系统和肠道屏障功能的调节。特别地，AHR参与必需氨基酸L-色氨酸（L-Trp）的微生物衍生的代谢物的结合。虽然肠道微生物组的各种成员现在已被证明参与产生激活AHR的L-Trp的生物活性衍生物的途径，但皮肤中的情况在很大程度上仍然难以捉摸。在项目1中，我们的目标是产生证据支持AHR信号作为微生物-宿主相互作用的关键参与者的作用，维持皮肤稳态，并在受到干扰时促进慢性皮肤炎症。我们正在研究健康的皮肤和不同的慢性炎症性皮肤病，如特应性皮炎和银屑病，这已被证明取决于AHR信号。申请人将从项目1的独特物理生物材料集合中挖掘数据集，并联合收割机这些数据集与最近可用的公共数据集（包括单细胞RNA-Seq数据）以及新生成的转录组和微生物组分析。在此，申请人将基于这些多组学数据集来研究以下具体目标：（1）揭示在稳态和慢性皮肤炎症期间Trp-催化剂依赖性皮肤AHR信号传导的微生物驱动的动力学。(2)定义角质形成细胞、感觉神经元和雪旺细胞作为AHR配体介导体外微生物-宿主相互作用的细胞靶点的功能后果。(3)通过微生物诱导的AHR信号在小鼠和人体内调节皮肤稳态和慢性皮肤炎症。这项研究的结果可能有助于了解AHR信号在微生物与宿主相互作用途径中的作用。它可以识别重要的“有益”与“有害”微生物及其产物，并基于AHR靶向定义新的策略，这有助于维持皮肤稳态和治疗性调节皮肤炎症。