Neurotransmitter Regulation of Immunity Through Effects on Endothelial Cells

神经递质通过影响内皮细胞调节免疫

• 批准号: 8702657
• 负责人: RICHARD David GRANSTEIN
• 金额: $ 22.37万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702657
• 关键词: Adrenergic Agents; Affect; Anatomy; Antigen Presentation; Antigen-Presenting Cells; Atopic Dermatitis; Autoimmune Diseases; Blood Vessels; CD4 Positive T Lymphocytes; Calcitonin Gene-Related Peptide; Caring; Cell Differentiation process; Cells; Cutaneous; Data; Dendritic Cells; Dermal; Development; Disease; Endothelial Cells; Engineering; Event; Exanthema; Functional disorder; Health; Helper-Inducer T-Lymphocyte; Herpes Simplex Infections; Human; ITGAM gene; Imiquimod; Immune; Immune response; Immune system; Immunity; Immunization; Immunobiology; Individual; Infectious Agent; Inflammatory; Interferons; Interleukin-17; Interleukin-4; Interleukin-6; Knockout Mice; Leishmania; Lymphatic; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Nature; Nerve; Nervous system structure; Neuropeptides; Neurophysiology - biologic function; Neurotransmitter Receptor; Neurotransmitters; Norepinephrine; Outcome; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Peptides; Pharmaceutical Preparations; Physiological Processes; Population; Preventive Intervention; Psoriasiform Dermatitis; Psoriasis; Public Health; RAMP1; Regulation; Regulatory Pathway; Research; Role; Sensory; Severities; Signal Transduction; Skin; Stress; System; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Tumor Necrosis Factor-alpha; Work; adrenergic; base; body system; cost; cytokine; design; economic impact; immune function; in vivo; insight; interleukin-22; langerin; lymph nodes; monocyte; nerve supply; neurotransmitter release; novel; novel strategies; peptide B; pituitary adenylate cyclase activating polypeptide; receptor; relating to nervous system; research study; response; skin disorder

DESCRIPTION (provided by applicant): This application proposes to study a recently discovered novel mechanism by which neurotransmitters (NTs) regulate the character and magnitude of T helper (Th) cell responses. Preliminary data demonstrate that NTs can act on endothelial cells (ECs), which then direct the types of immune responses generated in the course of antigen presentation by Langer- hans cells (LCs) to T cells. This novel concept is based on preliminary data showing that exposure of ECs to either (a) the neuropeptide calcitonin gene-related peptide (CGRP) (acting through the CGRP type 1 receptor) or (b) the adrenergic NT norepinephrine (NE), prior to addition to cultures of LCs presenting Ag to T cells, results in an increase in the release of IL-17A (a key cytokine in the pathophysiology of psoriasis) and a decrease in interferon-γ. Bias of Ag presentation toward an IL-17A response via NE or CGRP effects on ECs may explain exacerbation of Th17 cell-mediated diseases by stress. Innervation of dermal blood vessels, lymphatics (probably) and lymph nodes by both sensory and sympathetic nerves provides an anatomic substrate by which NTs can impact immune cells via ECs. The in vivo relevance of this pathway is supported by the observation that innervation of the skin is important for the expression of human psoriasis and that the rash in murine models of psoriasiform dermatitis depends on innervation. The discovery of this regulatory pathway may have important implications for a more complete understanding of cutaneous immunity, particularly in pathologic states. We hypothesize that the nervous system regulates the immune system toward particular types of responses by regulating the differentiation pathway of responsive CD4+ T cells through release of NTs acting on EC targets. We will explore this hypothesis in 2 aims: Aim 1A. To determine if CGRP, PACAP, VIP, NE or EPI regulate the outcome of Ag presentation by LCs to responsive CD4+ T cells through actions on ECs. We will test the generality of the hypothesis by studying other relevant skin Ag presenting cells, including dermal dendritic cells (DDCs) and monocyte-derived DCs (as a surrogate for inflammatory dermal DCs). Aim1B. To identify the cell and molecular biologic events in ECs induced by NTs that regulate Th cell differentiation during Ag presentation. We will test the importance of secreted molecules and cell-cell contact. Aim 2: To test the in vivo relevance of NT-induced EC signaling through the use of inducible, conditional KO mice where the expression of the relevant NT receptors is inactivated in EC. As we have determined that the CGRP type 1 receptor mediates the effect of CGRP in this pathway, we will initially generate mice in which we can incactivate the CGRP type 1 receptor and test the role of signaling through this receptor on immune responsiveness and on the development of rash in a a model of psoriasiform dermatitis. These studies will provide insight into the role of the nervous system in regulating skin immune responses, providing a better understanding of pathophysiology in the skin and creating a rational basis for developing drugs that can modulate skin immune responses, including some that may act via EC receptors. Since vessels in many tissues are innervated, our work may serve as a paradigm for the regulation of immune function in other tissues. It will enhance our appreciation of interactions between the nervous and immune systems, and may provide insights into autoimmune disorders and regulation of the immune response to cancer.

描述（由申请人提供）：本申请提出研究最近发现的神经递质（NT）调节T辅助（Th）细胞应答的特征和幅度的新机制。初步数据表明，NT可以作用于内皮细胞（EC），然后将Langer-hans细胞（LC）在抗原呈递过程中产生的免疫应答类型引导至T细胞。这一新的概念是基于初步的数据显示，暴露于（a）神经肽降钙素基因相关肽（CGRP）（通过CGRP 1型受体起作用）或（B）肾上腺素能NT去甲肾上腺素（NE），然后加入到将Ag呈递给T细胞的LC培养物中，导致IL-17 A（银屑病病理生理学中的关键细胞因子）释放增加和干扰素-γ减少。通过NE或CGRP对EC的作用，Ag呈递朝向IL-17 A应答的偏倚可以解释应激导致的Th 17细胞介导的疾病的恶化。感觉神经和交感神经对真皮血管、淋巴管（可能）和淋巴结的神经支配提供了一个解剖学基础，NT可以通过EC影响免疫细胞。该途径的体内相关性得到以下观察结果的支持：皮肤的神经支配对于人银屑病的表达是重要的，并且银屑病样皮炎的鼠模型中的皮疹依赖于神经支配。这一调节途径的发现可能对更全面地了解皮肤免疫，特别是在病理状态下的皮肤免疫具有重要意义。我们假设神经系统通过释放作用于EC靶点的NT来调节应答性CD 4 + T细胞的分化途径，从而调节免疫系统对特定类型的应答。我们将在两个目标中探索这个假设：目标1A。研究CGRP、PACAP、VIP、NE或EPI是否通过对EC的作用调节LC向应答性CD 4 + T细胞呈递Ag的结果。我们将通过研究其他相关的皮肤抗原呈递细胞，包括真皮树突状细胞（DDC）和单核细胞衍生的DC（作为炎症真皮DC的替代品）来测试该假设的一般性。目标1B。目的：探讨NTs诱导内皮细胞发生的细胞和分子生物学事件，NTs在抗原递呈过程中调节Th细胞的分化。我们将测试分泌分子和细胞间接触的重要性。目标二：通过使用诱导型条件性KO小鼠（其中相关NT受体的表达在EC中失活），测试NT诱导的EC信号传导的体内相关性。由于我们已经确定CGRP 1型受体介导CGRP在该途径中的作用，我们将首先产生小鼠，其中我们可以灭活CGRP 1型受体，并在银屑病样皮炎模型中测试通过该受体的信号传导对免疫应答和皮疹发展的作用。这些研究将深入了解神经系统在调节皮肤免疫反应中的作用，更好地了解皮肤的病理生理学，并为开发可以调节皮肤免疫反应的药物（包括一些可能通过EC受体起作用的药物）奠定合理的基础。由于许多组织中的血管受神经支配，我们的工作可以作为其他组织中免疫功能调节的范例。它将增强我们对神经和免疫系统之间相互作用的理解，并可能提供对自身免疫性疾病和癌症免疫反应调节的见解。