Mast cells in skin innate immune defense

皮肤先天免疫防御中的肥大细胞

• 批准号: 10333319
• 负责人: Anna Di Nardo
• 金额: $ 50.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333319
• 关键词: Ablation; Area; Atopic Dermatitis; Bacteria; Binding Sites; Biochemical; Biological Assay; Biology; Biophysics; Blood; CCL2 gene; CRISPR/Cas technology; Cell Maturation; Code; Data; Data Analyses; Dendritic Cells; Dermal; Dermis; Development; Disease; Environment; Exhibits; Failure; Fibroblasts; Gene Expression; Genes; Goals; Homeostasis; Human; Hypersensitivity; IL8 gene; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin-10; Interleukin-13; Interleukin-4; Interleukins; Literature; Measures; Mediating; Mediator of activation protein; Microbe; Modeling; NFKBIA gene; Organism; Pathway interactions; Peptides; Phenotype; Proteins; Publishing; Role; Science; Signal Transduction; Skin; TLR2 gene; Therapeutic; Virus; Work; commensal bacteria; conditioning; cytokine; design; dysbiosis; fighting; in vivo Model; insight; mast cell; microbiome; novel; prevent; receptor; response; skin disorder; transcriptome

ABSTRACT We have demonstrated that mast cells entering the skin change phenotype triggered by contact with dermal fibroblasts (DF). In the skin, Mast Cells (MCs) down regulate their TLR2 and increase the expression of genes that downregulate the NFB, a known inflammatory pathway. This contributes to maintaining skin homeostasis and makes mast cell tolerant to commensal bacteria. We found that DKK2, a specific protein secreted by DFs, modulates the huMC NF–B pathway, by increasing gene expression of TNFAIP3 (A20) and NFKBIA in huMCs. This modulation results in a decreased inflammatory response to commensal bacteria. In this proposal, we will clarify the mechanisms of DF - MC signaling, which induces a MC skin tolerant phenotype. This is an important mechanism for skin inflammation and atopic dermatitis (AD) in particular. We will present preliminary data that show that in AD, DFs fail to maintain human MC (huMC) tolerance to commensal bacteria which allows huMC to release proinflammatory cytokines. The idea that inflammatory diseases develop because MC tolerance is broken represents a shift in science paradigm. This work will identify the mechanisms underlying the roles of huMCs in building and breaking tolerance to the skin’s rich environment. We propose the followings: 1. To determine whether TNFAIP3 (A20) and NFKBIA in human MCs are required for preventing proinflammatory interleukin responses (tolerance) to commensal supernatant. In Aim 1 of this proposal, we will use a variety of structural, biophysical, biochemical, and functional assays to determine how dermal MCs collaborate with DFs. More specifically, we will analyze the MC expression of the NF–B related genes, TNFAIP3 (A20) and NFKBIA, as well as receptors related to the innate immune system in dermal huMCs. 2. To confirm that MC tolerance can be induced by DKK2 from DFs In Aim 2, we will determine whether DF DKK2 is required for inducing huMC tolerance to commensal supernatant and whether different DF sub-populations vary in their ability to induce tolerance in huMCs. 3. To confirm that DF-induced MC tolerance to commensal bacteria is critical for suppressing human skin inflammation. In Aim 3 of this proposal we will look at the consequences of the failure of huMCs to maintain tolerance and their role in skin inflammation, specifically in Atopic Dermatitis skin.

抽象的 我们已经证明，进入皮肤的肥大细胞会因与真皮接触而引发表型改变 成纤维细胞（DF）。在皮肤中，肥大细胞 (MC) 下调 TLR2 并增加基因表达 下调 NFκB（一种已知的炎症途径）。这有助于维持皮肤稳态 并使肥大细胞对共生细菌具有耐受性。我们发现 DKK2，一种由 DF 分泌的特定蛋白， 通过增加 TNFAIP3 (A20) 和 NFKBIA 的基因表达来调节 huMC NF–κB 通路 huMC。这种调节导致对共生细菌的炎症反应减少。在这个 该提案中，我们将阐明 DF - MC 信号传导的机制，该信号诱导 MC 皮肤耐受表型。 这是皮肤炎症尤其是特应性皮炎（AD）的重要机制。我们将呈现 初步数据表明，在 AD 中，DF 无法维持人类 MC (huMC) 对共生细菌的耐受性 它允许 huMC 释放促炎细胞因子。炎症性疾病发展的观点 因为 MC 耐受性被打破代表着科学范式的转变。这项工作将确定机制 huMC 在建立和打破对皮肤丰富环境的耐受性方面的作用。 我们提出以下建议： 1. 确定人类 MC 中的 TNFAIP3 (A20) 和 NFKBIA 是否需要预防 促炎白细胞介素对共生上清液的反应（耐受性）。在这个目标1中 根据建议，我们将使用各种结构、生物物理、生化和功能测定来 确定真皮 MC 如何与 DF 协作。更具体地说，我们将分析 MC 表达式 NF-κB 相关基因、TNFAIP3 (A20) 和 NFKBIA，以及与先天性相关的受体 真皮 huMC 中的免疫系统。 2. 确认来自DF的DKK2可以诱导MC耐受 在目标 2 中，我们将确定 DF DKK2 是否是诱导 huMC 对共生体耐受所必需的 上清液以及不同 DF 亚群在 huMC 中诱导耐受性的能力是否存在差异。 3. 确认 DF 诱导的 MC 对共生细菌的耐受性对于抑制 人体皮肤炎症。 在该提案的目标 3 中，我们将研究 huMC 未能维持耐受性的后果 及其在皮肤炎症中的作用，特别是在特应性皮炎皮肤中。