Role of neurokinin 1 receptor signaling in keratinocytes in allergic contact dermatitis

角质形成细胞中神经激肽 1 受体信号传导在过敏性接触性皮炎中的作用

基本信息

批准号：
10581825
负责人：
Adriana T Larregina
金额：
$ 59.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581825
关键词：
Address Affect Affinity Allergic Contact Dermatitis Binding CD8B1 gene Cell Communication Cells Chronic Disease Collaborations Cutaneous Data Dendritic Cells Development Dinitrochlorobenzene Disease Environment Epithelial Cells Exhibits Exposure to G Protein-Coupled Receptor Signaling GTP-Binding Protein alpha Subunits, Gs Generations Haptens Health Human Hypersensitivity Immune response Immunity Immunotherapy Impairment In Vitro Inflammasome Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Leukocytes Maintenance Mediating Mediator of activation protein Messenger RNA Modeling Molecular Mus Neuroimmune Neuropeptides Nuclear Translocation PPBP gene Pathogenesis Pathogenicity Pathway interactions Pattern recognition receptor Penetration Peptide Signal Sequences Peptides Phenotype Play Prevalence Prevention therapy Proteins Publications Publishing Receptor Activation Receptor Signaling Role Signal Pathway Signal Transduction Site Skin Substance P Substance P Receptor T cell response T memory cell T-Cell Activation T-Lymphocyte TC1 Cell Testing Work adaptive immune response chronic inflammatory skin cytokine cytotoxic effector T cell exosome experimental study extracellular vesicles immunoregulation in vivo insight intercellular communication keratinocyte microvesicles mouse model neuroinflammation public health relevance receptor receptor function response skin disorder therapy development vesicular release

项目摘要

ABSTRACT Allergic contact dermatitis (ACD) is a highly common chronic inflammatory skin disease initiated by skin exposure to a hapten, which triggers local neuroinflammatory responses and promotes the activation of pathogenic Type 1 biased effector T cells that sustain the chronicity of the disease. There is an unmet need for specific immunotherapies to treat ACD, and development of these treatments requires a thorough understanding of the cellular and molecular mechanisms of the disease. During hapten penetration of the skin, signaling the neurokinin-1 receptor (NK1R) by the proinflammatory neuropeptides substance P and hemokinin-1 promotes cutaneous inflammation. This proinflammatory skin environment is required for the T cell-stimulatory and Type 1 biasing function of resident dendritic cells (DCs). Because lacking NK1R in mice impairs the development of ACD it has been proposed that blockade of the receptor could be beneficial to treat the disease. Understanding the impact of NK1R-signaling in the immune response to haptens is of fundamental relevance for therapies attempting to inhibit the function of the receptor to treat ACD. Nonetheless, the cellular and molecular mechanisms and the pathogenic consequences of hapten- mediated NK1R activation in the skin remain to be elucidated. Keratinocytes constitute the first line of defense affected by contact sensitizers and they have per se a relevant role in innate and adaptive components of skin-initiated immune responses. Keratinocytes are the main cell subset that expresses constitutively the NK1R. Using NK1Rfl/fl mice, we published that specific deletion of the NK1R in keratinocytes impairs the synthesis and secretion of IL-1β, a cytokine necessary for the activation of T-cell stimulatory DCs, and inhibits the innate and adaptive immune responses of ACD. Therefore, we hypothesize that: “Keratinocytes are early cell targets of hapten-mediated NK1R-signaling, and that they are required to generate the proinflammatory skin environment that supports the innate and effector immune responses of ACD”. We will address this hypothesis in the following specific aims. Specific aim 1 will analyze the mechanisms of the proinflammatory effects caused by NK1R-signaling in keratinocytes exposed to haptens. Specific aim 2 will analyze the mechanisms of intercellular communication by which keratinocytes interact with skin resident DCs to promote their T cell stimulatory functions during hapten initiated skin inflammation. Specific aim 3 will analyze the role of the NK1R-signaling exclusively in keratinocytes in the generation of the effector and memory T cells of ACD. Our studies include in vitro and in-vivo mouse models and ex-vivo human skin models to test the translational relevance of our experiments. If successful, the data generated through this application will provide highly relevant missing information for the development of efficient specific therapies for the prevention and treatment of ACD.

抽象的过敏性接触性皮炎（ACD）是一种非常常见的慢性炎症性皮肤病，由皮肤暴露引起半抗原，触发局部神经炎症反应并促进致病型的激活 1 维持疾病慢性的偏向效应 T 细胞对于特定的需求尚未得到满足。免疫疗法治疗 ACD，这些疗法的开发需要对 ACD 的透彻了解该疾病的细胞和分子机制。在半抗原渗透皮肤过程中，促炎细胞向神经激肽-1 受体 (NK1R) 发出信号神经肽 P 物质和血激肽 1 会促进皮肤炎症。常驻树突状细胞 (DC) 的 T 细胞刺激和 1 型偏向功能需要环境。由于小鼠体内缺乏 NK1R 会损害 ACD 的发展，因此有人建议阻断受体可能有助于了解 NK1R 信号传导对免疫系统的影响。对半抗原的反应对于试图抑制受体功能的治疗具有根本意义然而，治疗 ACD 的细胞和分子机制以及半抗原的致病后果。皮肤中介导的 NK1R 激活仍有待阐明。角质形成细胞构成受接触敏化剂影响的第一道防线，它们本身具有皮肤引发的免疫反应的先天性和适应性成分中的相关作用是主要的。使用 NK1Rfl/fl 小鼠，我们发表了组成型表达 NK1R 的细胞亚群的特定删除。角质形成细胞中的 NK1R 会损害 IL-1β 的合成和分泌，IL-1β 是激活所需的细胞因子 T 细胞刺激性 DC，并抑制 ACD 的先天性和适应性免疫反应。认为：“角质形成细胞是半抗原介导的 NK1R 信号传导的早期细胞靶标，并且它们需要产生支持先天和效应细胞的促炎皮肤环境 ACD 的免疫反应”，我们将在以下具体目标 1 中解决这一假设。分析暴露于环境的角质形成细胞中 NK1R 信号传导引起的促炎作用的机制具体目标 2 将分析角质形成细胞的细胞间通讯机制。与皮肤驻留 DC 相互作用，在半抗原启动皮肤过程中促进其 T 细胞刺激功能具体目标 3 将分析 NK1R 信号传导在角质形成细胞中的作用。我们的研究包括体外和体内小鼠模型。和离体人体皮肤模型来测试我们实验的转化相关性如果成功的话，数据。通过此应用程序生成的信息将为开发高效的解决方案提供高度相关的缺失信息。预防和治疗 ACD 的具体疗法。