Mast cells in skin innate immune defense

摘要 我们已经证明，进入皮肤的肥大细胞通过与真皮接触而改变表型。 成纤维细胞（DF）。在皮肤中，肥大细胞（MC）下调其TLR 2并增加基因表达 下调NF κ B B，一种已知的炎症途径。这有助于维持皮肤的稳态 并使肥大细胞对肠道细菌耐受。我们发现DKK 2，一种由DF分泌的特异性蛋白， 调节huMC NF-κ B B通路，通过增加TNF α IP 3（A20）和NF κ BIA的基因表达， huMC。这种调节导致对肠道细菌的炎症反应降低。在这 本研究将阐明DF - MC信号转导的机制，从而诱导MC皮肤耐受表型。 这是皮肤炎症和特应性皮炎（AD）的重要机制。我们将介绍 初步数据显示，在AD中，DF不能维持人MC（huMC）对肠道细菌的耐受性， 这允许huMC释放促炎细胞因子。炎症性疾病发展的观点 因为MC耐受性的打破代表了科学范式的转变。这项工作将确定 在建立和破坏对皮肤丰富环境的耐受性中，huMCs的作用是潜在的。 我们提出以下建议： 1.为了确定人类MC中的TNFAIP 3（A20）和NFKBIA是否是预防肿瘤所必需的， 促炎性白细胞介素应答（耐受性）。目标1 建议，我们将使用各种结构，生物物理，生物化学和功能测定， 确定真皮MC如何与DF合作。更具体地说，我们将分析MC表达式 NF-κ B B相关基因TNFAIP 3（A20）和NF κ BIA，以及与先天性免疫缺陷相关的受体。 真皮huMCs中免疫系统。 2.证实DF的DKK 2可诱导MC耐受 在目标2中，我们将确定DF DKK 2是否是诱导huMC对紫杉醇耐受所必需的。 不同DF亚群诱导huMC耐受性的能力是否不同。 3.为了证实DF诱导的MC对肠道细菌的耐受性对于抑制 人类皮肤炎症 在本提案的目标3中，我们将研究huMC未能维持耐受性的后果 以及它们在皮肤炎症中的作用，特别是在特应性皮炎皮肤中。

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.