The Microbiome Drives Masts Cell Recruitment in the Skin

微生物组驱动皮肤中肥大细胞的募集

• 批准号: 9044386
• 负责人: Anna Di Nardo
• 金额: $ 4.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044386
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Atopic Dermatitis; Bacteria; Biochemical; Biological Assay; Biological Models; Cell Communication; Cell Maturation; Cell Migration Pathway; Cell physiology; Cells; Communication; Cytoplasmic Granules; Data; Defect; Dermal; Dermis; Development; Disease; Endothelial Cells; Environment; Epithelial; Foundations; Future; Germ-Free; Growth Factor; Health; Homeostasis; Homing; Human; Immune response; Immune system; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Interleukin-1; Life; Ligands; Mediating; Methods; MicroRNAs; Modeling; Molecular; Mus; NF-kappa B; Natural Immunity; Organism; Pathway interactions; Phenotype; Play; Positioning Attribute; Production; Psoriasis; Receptor Signaling; Recruitment Activity; Regulation; Relative (related person); Role; Shapes; Signal Pathway; Signal Transduction; Skin; Surface; System; Testing; Toll-Like Receptor 2; Translating; Translational Research; Work; acquired immunity; antimicrobial; antimicrobial peptide; base; cell motility; commensal microbes; cytokine; fighting; in vivo; keratinocyte; lipoteichoic acid; mast cell; microbiome; mouse model; receptor; reconstitution; research study; response; trafficking

DESCRIPTION (provided by applicant): Despite the importance of mast cells (MCs) in innate and acquired immunity, their development and recruitment into the skin is not well understood. Our findings suggest that the skin microbiome has a strong influence on migrating and, in particular, maturing MCs in the skin. Based on our preliminary data, we have demonstrated that bacterial products at the skin surface participate in the regulation of MC antimicrobial functions, homing to the skin, and help them respond to their survival growth factor, SCF. Even more important is the ability of the microbiome to induce an anti-inflammatory phenotype on human MCs that contributes to maintaining skin homeostasis, which helps avoid unnecessary inflammation. Antibiotic exposure, and a pseudo-aseptic environment, have the potential to alter the skin microbiome selectively and may be the cause of the increasing incidence of human disorders such as atopic dermatitis. We hypothesize that bacterial products, increase mast cell recruitment and are responsible for maintaining high levels of antimicrobial peptides (AMPs) and a low pro-inflammatory cytokine profile. A humanized mouse model system will enable the simultaneous study of both human MC migration pathways and TLR innate immune responses in a genetically adaptable organism, thereby translating our findings to human skin. We propose the following: a) Determine whether bacterial products from the skin microbiome are required for normal mast cell localization and function. The use of germ free and antibiotic treated mice will allow us to test whether disruption of the normal skin microbiome results in improper localization and function in vivo and whether reconstituting the microbiome can reverse these effects. Because human MCs may have a different sensitivity to the microbiome, we will test our findings on human MCs (huMCs) to provide a foundation for future translational research. b) Clarify the signaling pathways that are responsible for MC sensing the skin microbiome and how activation of these pathways affects MC function. We will focus on characterizing the MC receptors involved in sensing bacterial byproducts. The aspects to be studied: 1. Commensal activity directly on MC receptors (TLR ligands), 2. Commensal activity on keratinocytes that generate ligands (SCF, IL-1, and S1P) for MC receptors, and 3. Commensal activity on Endothelial cells (SCF) that generate ligands for MC receptors. c) Determine how MC interaction with the microbiome modulates intracellular pathways in skin MCs and affects their function. Our preliminary data show that bacterial byproducts modulate huMCs maturation and activation through NF-kB, S1P and intracellular sphingokinases (Sphks) pathways to produce S1P; we have found that LTA and other commensal fractions induce the expression of specific miRNAs that interfere with TLR-NF-kB signaling.

描述（由申请人提供）：尽管肥大细胞（MC）在先天性和获得性免疫中的重要性，但其发育和招募到皮肤中的情况尚未得到充分了解。我们的研究结果表明，皮肤微生物组对迁移，特别是皮肤中成熟的MC有很大的影响。基于我们的初步数据，我们已经证明皮肤表面的细菌产物参与MC抗微生物功能的调节， 归巢到皮肤，并帮助他们回应他们的生存生长因子，SCF。更重要的是微生物组在人类MC上诱导抗炎表型的能力，这有助于维持皮肤稳态，这有助于避免不必要的炎症。抗生素暴露和伪无菌环境有可能选择性地改变皮肤微生物组，并可能是人类疾病（如特应性皮炎）发病率增加的原因。我们假设细菌产物增加肥大细胞募集，并负责维持高水平的抗菌肽（AMP）和低促炎细胞因子谱。人源化小鼠模型系统将能够同时研究人类MC迁移途径和遗传适应性生物体中的TLR先天免疫应答，从而将我们的发现转化为人类皮肤。我们建议如下：a）确定来自皮肤微生物组的细菌产物是否是正常肥大细胞定位和功能所需的。使用无菌和抗生素治疗的小鼠将使我们能够测试正常皮肤微生物组的破坏是否会导致体内定位和功能不正确，以及重建微生物组是否可以逆转这些影响。由于人类MCs可能对微生物组具有不同的敏感性，因此我们将在人类MCs（huMCs）上测试我们的发现，为未来的转化研究提供基础。B）阐明负责MC感知皮肤微生物组的信号传导途径以及这些途径的激活如何影响MC功能。我们将专注于表征参与传感细菌副产物的MC受体。研究内容：1.直接对MC受体（TLR配体）的共生活性，2.对产生MC受体配体（SCF、IL-1和S1 P）的角质形成细胞的协同活性，和3.对生成MC受体配体的内皮细胞（SCF）具有协同活性。c）确定MC与微生物组的相互作用如何调节皮肤MC中的细胞内途径并影响其功能。我们的初步数据显示，细菌副产物通过NF-kB、S1 P和细胞内鞘氨醇激酶（Sphks）途径调节huMCs的成熟和活化，以产生S1 P;我们发现LTA和其他细胞组分诱导干扰TLR-NF-kB信号传导的特异性miRNA的表达。