Skin microbiome regulation of the sebum-immune axis

皮肤微生物组对皮脂免疫轴的调节

• 批准号: 10732282
• 负责人: Elizabeth Anne Grice
• 金额: $ 68.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732282
• 关键词: Adaptive Immune System; Adaptor Signaling Protein; Adoptive Transfer; Affect; Androgen Receptor; Androgens; Antigens; Atopic Dermatitis; Biology; Cell Count; Cell Line; Cells; Cellular Immunology; Cellular biology; Chemicals; Cutaneous; Cytokine Receptors; Data; Disease; Ensure; Environment; Epithelium; Exhibits; Family; Feedback; Gene Expression; Genes; Genetic; Germ-Free; Gland; Goals; Growth; Health; Homeostasis; Hormones; Human; Hypersensitivity skin testing; IL1R1 gene; Immune; Immune system; Immunologics; Infection; Infectious Skin Diseases; Innate Immune System; Interleukin-1; Interleukin-1 Receptors; Interleukin-13; Interleukin-4; Investigation; Lipids; Mediating; Microbe; Modeling; Molecular Immunology; Molecular and Cellular Biology; Mus; Pathogenesis; Pathogenicity; Phenotype; Process; Proliferating; Regulation; Reporter; Reporting; Research; Role; Sebaceous Glands; Sebum; Signal Pathway; Signal Transduction; Skin; Source; Stains; Staphylococcus aureus; Staphylococcus epidermidis; T cell therapy; T-Cell Activation; T-Lymphocyte; TSLP gene; Testing; Toll-like receptors; Water; antimicrobial; antimicrobial peptide; commensal microbes; cytokine; defense response; gain of function; gland development; in vivo; insight; keratinocyte; loss of function; microbiota; migration; multidisciplinary; novel; overexpression; pathogen; pharmacologic; receptor; repaired; response; skin barrier; skin microbiome; skin microbiota

Summary The skin forms a protective barrier against harmful substances and pathogens that we contact through our immediate environment. Specialized glands in the skin known as sebaceous glands secrete sebum, a lipid-rich substance with anti-microbial peptides (AMPs) that enhances the physical, chemical, and immunologic barrier function of the skin. This proposal describes a 5-year research plan focusing on the novel concept that the skin microbiome regulates a newly described immune-mediated sebum axis as a feedback mechanism to enhance skin barrier function and to create an optimal skin microenvironment. We have recently reported that sebum secretion can be regulated by immune cells in response to a keratinocyte-derived cytokine called thymic stromal lymphopoietin (TSLP). In this process, which we call the immune-sebum axis, TSLP stimulates T cells directly through their TSLP receptor (TSLP-R), which induces their migration to the sebaceous glands to promote sebum secretion in an IL-4/13-dependent manner. We now provide preliminary data suggesting that the trigger of the immune-sebum axis could be the skin microbiome. We find that compared to conventionally raised mice, the skin of germ-free mice contains significantly fewer T cells, exhibits ~50% reduction in sebum secretion, and displays lower expression of TSLP, sebum synthesis- related genes, and AMPs. In addition, we found that mice lacking the IL-1 receptor or MyD88 (a molecule critical for signaling downstream of IL-1 family cytokine receptors and Toll-like receptors) also display ~50% reduction in sebum secretion. Thus, we propose that a feedback mechanism exists to maintain homeostasis of the skin microenvironment, whereby skin microbes promote sebum secretion, which in turn controls their growth. Based on these preliminary data, we hypothesize that skin microbes induce the IL-1/MyD88 signaling pathway in the skin to promote sebum secretion and skin barrier function in a TSLP- stimulated T cell-derived IL-4/13-dependent manner. We will test this hypothesis in 3 separate aims. Aim 1 will investigate how the skin microbiota and MyD88 regulate sebum secretion. Aim 2 will probe how IL-4/13 derived from TSLP-stimulated T cells affects sebaceous gland function. Aim 3 will test whether the skin microbiota and TSLP affect skin barrier function and protects against pathogenic skin infection in a sebum- dependent manner. This multidisciplinary project will be led by two co-PIs (Drs. Kambayashi and Grice), who share complementary expertise. Dr. Kambayashi is an expert in T cell biology, cellular immunology, and signal transduction. Dr. Grice is an expert in skin barrier function and skin microbiota. Other collaborators include Dr. Amanda Nelson, as an expert in sebaceous gland biology and Dr. Sunny Wong as an expert in sebaceous gland development. This investigation will provide novel insight into how the skin microbiome engages both the innate and adaptive immune system to promote optimal skin barrier function for the host.

总结 皮肤形成了一个保护屏障，抵御我们通过皮肤接触的有害物质和病原体。 直接环境。皮肤中专门的腺体称为皮脂腺，分泌皮脂，一种富含脂质的物质， 一种含有抗菌肽（AMP）的物质，可增强物理、化学和免疫屏障 皮肤的功能。该提案描述了一项为期5年的研究计划，重点是皮肤 微生物组调节一种新描述的免疫介导的皮脂轴作为一种反馈机制， 皮肤屏障功能和创造最佳皮肤微环境。 我们最近报道，免疫细胞可以调节皮脂分泌， 角化细胞衍生的细胞因子称为胸腺基质淋巴细胞生成素（TSLP）。在这个过程中，我们称之为 在免疫-皮脂轴中，TSLP直接通过其TSLP受体（TSLP-R）刺激T细胞，其诱导 它们迁移到皮脂腺，以IL-4/13依赖性方式促进皮脂分泌。我们现在 提供了初步数据，表明免疫-皮脂轴的触发因素可能是皮肤微生物组。 我们发现，与常规饲养的小鼠相比，无菌小鼠的皮肤含有明显较少的T 细胞，表现出约50%的皮脂分泌减少，并表现出较低的TSLP表达，皮脂合成- 相关基因和AMP。此外，我们发现缺乏IL-1受体或MyD 88（一种分子）的小鼠， 对于IL-1家族细胞因子受体和Toll样受体的下游信号传导至关重要）也显示约50% 减少皮脂分泌。因此，我们认为存在一种反馈机制来维持体内平衡， 皮肤微环境，其中皮肤微生物促进皮脂分泌，这反过来控制它们的 增长 基于这些初步数据，我们假设皮肤微生物诱导IL-1/MyD 88 在TSLP中促进皮肤中的皮脂分泌和皮肤屏障功能的信号传导途径， 刺激T细胞来源的IL-4/13依赖性方式。我们将在三个不同的目标中测试这个假设。要求1 将研究皮肤微生物群和MyD 88如何调节皮脂分泌。目标2将探讨IL-4/13如何 来源于TSLP刺激的T细胞影响皮脂腺功能。目标3将测试皮肤是否 微生物群和TSLP影响皮肤屏障功能，并防止皮脂中的病原性皮肤感染。 依赖的方式。这一多学科项目将由两名共同PI（Kambayashi博士和Grice博士）领导， 分享互补的专业知识。Kambayashi博士是T细胞生物学、细胞免疫学和信号学方面的专家 转导Grice博士是皮肤屏障功能和皮肤微生物群的专家。其他合作者包括博士。 阿曼达纳尔逊，作为一个专家在皮脂腺生物学和博士Sunny黄作为一个专家在皮脂腺 腺体发育这项研究将提供新的见解，了解皮肤微生物组如何参与皮肤和皮肤细胞之间的相互作用。 天然和适应性免疫系统，以促进宿主的最佳皮肤屏障功能。