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

最近的研究结果表明，人类健康是“多有机体的”。共生或致病微生物与它们定植的宿主之间的相互作用是维持体内平衡和引发疾病的核心。关于皮肤微生物组及其在各种皮肤病中的变化的详细知识现在是可用的。然而，微生物与宿主皮肤细胞之间的特定相互作用，包括生物间细胞间通信的途径，尚不清楚。最近，人们发现一种众所周知的通讯受体，即芳烃受体（AHR）在肠道内微生物与宿主的相互作用中起着关键作用。AHR是肠道微生物群产生和释放代谢物的关键传感器，参与调节粘膜免疫系统和肠道屏障功能。特别是，AHR参与必需氨基酸l-色氨酸（L-Trp）的微生物衍生代谢物的结合。尽管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 -色氨酸的生物活性衍生物的途径，但皮肤的情况仍然难以捉摸。在项目1中，我们的目标是提供证据支持AHR信号在微生物-宿主相互作用中发挥关键作用，维持皮肤稳态，当受到干扰时，促进慢性皮肤炎症。我们正在研究健康皮肤和独特的慢性炎症性皮肤病，如特应性皮炎和牛皮癣，这些疾病已被证明依赖于AHR信号。申请人将从项目1的独特物理生物材料收集中挖掘数据集，并将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相结合。在这里，申请人将建立在这些多组学数据集的基础上，研究以下具体目标：(1)在稳态和慢性皮肤炎症期间，揭示trp分解代谢依赖的皮肤AHR信号的微生物驱动动力学。(2)确定AHR配体在体外介导微生物-宿主相互作用时在角质形成细胞、感觉神经元和雪旺细胞中的功能后果。(3)在小鼠和人体内验证微生物诱导的AHR信号对皮肤稳态和慢性皮肤炎症的调节。这项研究的发现可能会揭示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，并确定基于AHR靶向的新策略，这有助于维持皮肤稳态和治疗性地调节皮肤炎症。

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.