Cell type-specific regulation and function of the AHRR in skin inflammation and allergy

AHR信号通过几种机制控制，以确保适当调节异生物质代谢和免疫过程。细胞色素P450（CYP1A1、CYP1B1和CYP1A2）家族的酶和AHR阻遏物（AHRR）是AHR的靶基因，也是AHR激活的重要反馈控制机制。为了分析AHRR在体内的功能，我们产生了AHRR报告小鼠，发现AHRR表达在屏障器官的免疫细胞中是强烈的，如肠道和皮肤，而在上皮细胞中不太明显。然而，AHR依赖的CYP 1家族成员可能在上皮细胞中更活跃。因此，我们假设，AHR信号可能在不同的细胞类型中受到不同的调节，这可能对理解皮肤中的AHR功能至关重要。鉴于上皮细胞和免疫细胞在屏障器官中相互作用的重要性，我们希望探索AHRR和AHR依赖性CYP 1酶在皮肤炎症和过敏中的功能。我们将在接触性超敏反应和特应性皮炎（如皮肤炎症）小鼠模型中比较AHRR缺陷小鼠、AHR依赖性CYP 1酶缺陷小鼠和CYP 1酶和AHRR均缺陷小鼠的免疫病理学和疾病严重程度。此外，我们想解决的问题是，AHRR和CYP 1的表达是如何在皮肤上皮细胞与免疫细胞的转录和表观遗传水平上进行调节，以及为什么AHRR在免疫细胞中的表达，但在角质形成细胞中的程度较低，是重要的AHR激活皮肤稳态，炎症和过敏。通过这种全球性的方法，我们还希望在这些细胞类型中鉴定新的差异调节靶基因，这些基因可能有助于单细胞水平上的AHR调节。为了测试上皮细胞中强制AHRR表达的假定有害作用，我们将产生小鼠以在体内细胞类型特异性地表达AHRR，并分析角质形成细胞中强制AHRR表达对皮肤稳态、屏障功能和过敏的影响。总之，在本项目中，我们打算阐明免疫细胞与角质形成细胞中不同调节机制的分子基础，以拓宽和加强对皮肤中AHR功能调节网络的认识。

AHR signalling is controlled via several mechanisms to ensure proper regulation of xenobiotic metabolism and immune processes. Enzymes of the cytochrome P450 (CYP) family, namely CYP1A1, CYP1B1 and CYP1A2 and the AHR repressor (AHRR) are AHR target genes and also important feedback control mechanisms of AHR activation. To analyse the function of AHRR in vivo, we generated AHRR-reporter mice and found that AHRR expression is intense in immune cells of barrier organs, such as gut and skin, and less pronounced in epithelial cells. AHR-dependent CYP1 family members, however, might be more active in epithelial cells. Therefore, we hypothesize, that AHR signalling might be regulated differentially in distinct cell types and this might be crucial for understanding AHR function in skin. Given the importance of the crosstalk of epithelial and immune cells at barrier organs, we want to explore the function of the AHRR and the AHR-dependent CYP1 enzymes in skin inflammation and allergy. We will compare the immunopathology and disease severity of AHRR-deficient mice, mice deficient for the AHR-dependent CYP1 enzymes and mice deficient for both, CYP1 enzymes and AHRR in mouse models of contact hypersensitivity and atopic dermatitis like skin inflammation. Further, we want to address the question how AHRR and CYP1 expression are regulated on transcriptional and epigenetic levels in skin epithelial cells versus immune cells and why AHRR expression in immune cells but to a lesser degree in keratinocytes is important for AHR activation during skin homeostasis, inflammation and allergy. With this global approach we also want to identify novel differentially regulated target genes in these cell types which might contribute to AHR regulation on a single cell level. To test a putative detrimental role of forced AHRR expression in epithelial cells we will generate mice to cell type-specifically express AHRR in vivo and analyze the impact of forced AHRR expression in keratinocytes for skin homeostasis, barrier function and allergy. In summary, in this project we intend to elucidate the molecular basis for the different regulation mechanism in immune cells versus keratinocytes to broaden and intensify the knowledge of regulatory networks of AHR function in skin.