Acne: a disease of lipid metabolism, microbiome and the immune response

摘要/项目总结 研究项目 UCLA/UCSD研究项目的总体目标是研究微生物组之间的相互作用， 痤疮中脂质代谢和宿主免疫反应。毛囊皮脂腺单位（PSebU）的微生物组， 痤疮病变发展的初始部位是易处理的，痤疮皮肤杆菌是优势细菌。C. 痤疮被认为是痤疮发病机制中的关键因素之一。UCLA/UCSD 研究项目基于我们最近使用转录组学，宏基因组学和脂质组学的发现， 建立目标，将这些不同的生物反应联系在一起，形成一个模型，可以解释 痤疮的发病机制。通过应用单细胞RNA测序（scRNA-seq）和空间测序，Modlin和 加洛实验室已经共同确定了特定的巨噬细胞和间充质干细胞成纤维细胞亚群 与相同患者的未受累皮肤相比，在痤疮病变中发生。令人惊讶的是，我们发现了一个 大量TREM 2巨噬细胞，先前在以脂质改变为特征的疾病中鉴定 在痤疮病变中表达脂质代谢和促炎基因程序。我们发现 角鲨烯是皮脂的一种成分，在体外诱导TREM 2巨噬细胞，而这些巨噬细胞不是抗菌剂， 部分原因是角鲨烯抑制了杀死C.粉刺。此外，委员会认为， 痤疮病变还含有独特的炎性成纤维细胞亚群， 轨迹并以TLR 2依赖的方式产生促炎性cathelicidin，这暗示了第一个 毛囊周围成纤维细胞作为痤疮炎症的关键贡献者。UCLA/UCSD研究 项目（Modlin，Gallo），“痤疮：脂质代谢，微生物组和免疫反应的疾病”，将 最初集中研究TREM 2巨噬细胞和脂肪形成成纤维细胞在糖尿病发病机制中的作用， 痤疮项目研究者将获得痤疮活检标本（Hata，Kim），然后解决 痤疮病变对微生物组和脂质代谢的免疫反应。研究项目将是 由UCLA生物信息学核心（Pellegrini，Yang）支持，以分析痤疮的scRNA-seq和空间-seq 病变，UCSD微生物学和宏基因组学核心（Gallo，奥尼尔）分离和表征C.痤疮 菌株，以及活组织检查标本和体外衍生的关键细胞类型的脂质组学分析（Bensinger，UCLA）。 最终，生物信息学核心将使用合并几何学来联合收割机从转录组学、宏基因组学和 脂质组学建立痤疮发病机制的网络模型。这些研究将提供新的 深入了解脂质代谢和皮肤微生物组如何塑造皮肤免疫反应， 对炎症有潜在的干预作用。

ABSTRACT / PROJECT SUMMARY Research Project The overall goal of UCLA/UCSD Research Project is to investigate the interaction between the microbiome, lipid metabolism and the host immune response in acne. The microbiome of the pilosebaceous unit (PSebU), the initial site where acne lesions develop, is tractable, with Cutibacterium acnes the dominant bacterium. C. acnes is considered to be one of the key contributing factors in the pathogenesis of acne. The UCLA/UCSD Research Project is based on our recent findings using transcriptomics, metagenomics and lipidomics, establishing the goal to link together these diverse biologic responses into a model that may explain the pathogenesis of acne. By applying single cell RNA-sequencing (scRNA-seq) and spatial-seq, the Modlin and Gallo labs have together identified specific macrophage and mesenchymal stem cell fibroblasts subpopulations that occur in acne lesions as compared to uninvolved skin from the same patients. Surprisingly, we detected a large population of TREM2 macrophages, previously identified in diseases characterized by altered lipid metabolism, in acne lesions expressing both lipid metabolism and pro-inflammatory gene programs. We found that squalene, a component of sebum, induced TREM2 macrophages in vitro that were not antimicrobial, in part because squalene inhibited production of and scavenged oxygen radicals that kill C. acnes. Furthermore, acne lesions also contain a unique inflammatory fibroblast subpopulation that undergoes an adipogenic trajectory and produces pro-inflammatory cathelicidin in a TLR2 dependent manner, implicating for the first time the perifollicular fibroblast as a critical contributor to acne inflammation. The UCLA/UCSD Research Project (Modlin, Gallo), “Acne: a disease of lipid metabolism, microbiome and the immune response”, will initially focus studies on the role of TREM2 macrophages and adipogenic fibroblasts in the pathogenesis of acne. The project investigators will obtain acne biopsy specimens (Hata, Kim), then address the link between the immune response in acne lesions to the microbiome and lipid metabolism. The Research Project will be supported by a UCLA Bioinformatics Core (Pellegrini, Yang) to analyze scRNA-seq and spatial-seq of acne lesions, a UCSD Microbiology and Metagenomics Core (Gallo, O’Neill) to isolate and characterize C. acnes strains, and lipidomics analysis (Bensinger, UCLA) of biopsy specimens and key cell types derived in vitro. Ultimately, Bioinformatics core will use mergeomics to combine data from transcriptomics, metagenomics and lipidomics to create a network model of the pathogenesis of acne. The proposed studies will provide new insights into how lipid metabolism and the skin microbiome shapes cutaneous immune responses contributing to inflammation, with the potential for intervention in skin disease.