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

• 批准号: 10707217
• 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
• 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/10707217
• 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; Generations; Haptens; Health; Human; Hypersensitivity; Immune response; Immunity; Immunotherapy; Impairment; In Vitro; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Interleukin-1 beta; Leukocytes; Maintenance; Mediating; Mediator; 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; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; TACR1 gene; 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

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.

摘要 变应性接触性皮炎（ACD）是一种常见的慢性炎症性皮肤病 半抗原，其触发局部神经炎性反应并促进致病型 1偏向的效应T细胞，维持疾病的慢性。有一个未得到满足的需要， 免疫疗法治疗ACD，这些治疗的发展需要彻底了解 疾病的细胞和分子机制。 在半抗原穿透皮肤的过程中，通过促炎性细胞因子向神经激肽-1受体（NK1R）发出信号， 神经肽P物质和血激肽-1促进皮肤炎症。这种促炎性皮肤 环境是T细胞刺激和驻留树突状细胞（DC）的1型偏向功能所必需的。 由于小鼠中缺乏NK1R会损害ACD的发展，因此已经提出阻断NK1R的表达可以抑制ACD的发展。 受体可能对治疗该疾病有益。了解NK1R信号传导在免疫系统中的影响 对半抗原的应答对于试图抑制受体功能的治疗具有根本的相关性 来治疗ACD尽管如此，半抗原的细胞和分子机制以及致病后果- 皮肤中介导的NK1R活化仍有待阐明。 角质形成细胞构成了受接触致敏物影响的第一道防线，它们本身具有 在皮肤引发的免疫应答的先天性和适应性组分中的相关作用。角质形成细胞是主要的 细胞亚群组成性表达NK1R。使用NK1Rfl/fl小鼠，我们发表了特定的缺失， 角质形成细胞中的NK1R损害IL-1 β的合成和分泌，IL-1 β是活化角质形成细胞所必需的细胞因子， 的T细胞刺激性DC，并抑制ACD的先天性和适应性免疫应答。所以我们 假设：“角化细胞是半抗原介导的NK 1 R信号传导的早期细胞靶点，并且它们 需要产生支持先天和效应的促炎皮肤环境， ACD的免疫应答"。我们将在以下具体目标中讨论这一假设。具体目标1将 分析NK1R信号在暴露于以下物质的角质形成细胞中引起的促炎作用的机制： 半抗原。具体目标2将分析角质形成细胞通过细胞间通讯的机制， 与皮肤驻留DC相互作用以促进它们在半抗原引发的皮肤中的T细胞刺激功能 炎症具体目标3将分析NK 1 R信号仅在角质形成细胞中的作用 ACD的效应和记忆T细胞的产生。我们的研究包括体外和体内小鼠模型 和离体人皮肤模型来测试我们实验的翻译相关性。如果成功，数据 通过此应用程序生成的信息将为开发高效的 用于预防和治疗ACD的特定疗法。