Does UV-induced Unconventional Mast Cell Migration Activate Immune Suppression?

紫外线诱导的非常规肥大细胞迁移是否会激活免疫抑制？

• 批准号: 7805509
• 负责人: Stephen E ULLRICH
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805509
• 关键词: Affect; Animals; Binding; Biopsy; CXCL12 gene; CXCR4 gene; Cancer Patient; Data; Dendritic Cells; Dermal; Development; Dinoprostone; Dose; Elements; Environmental Carcinogens; Event; Exposure to; Ficusin; Goals; Human; IL10 gene; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Infectious Agent; Inflammation; Interleukin-10; Interleukin-12; Interleukin-4; Interleukins; Laboratories; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Occupational; Platelet Activating Factor; Play; Production; Psoralens; Public Health; Reaction; Reagent; Research; Risk Factors; Role; Site; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Sunlight; Testing; Therapeutic Agents; Transcriptional Activation; UV induced; Ultraviolet Rays; carcinogenesis; cell motility; chemokine receptor; cyclooxygenase 2; cytokine; environmental agent; immune function; insight; lymph nodes; mast cell; microbial; migration; new therapeutic target; novel therapeutics; prevent; public health relevance; receptor; research study; sunlight-induced; ultraviolet

DESCRIPTION (provided by applicant): Ultraviolet (UV) radiation is a major environmental carcinogen and the primary cause of non-melanoma skin cancer. UV radiation is also immunosuppressive and the systemic immune suppression induced by UV exposure is a major risk factor for skin cancer induction. Previous findings from my lab have indicated that UV exposure activates a cytokine cascade (UV? PAF?PGE2 ?IL-4, ?IL-10? suppressed dendritic cell IL-12 production) that leads to systemic immune suppression. Because mast cells release many of the factors known to play a role in UV-induced systemic immune suppression, we focused on their role in the induction of immune suppression to gain a better understanding of the mechanisms involved. Mast cells clearly play an essential role in UV-induced immune suppression because UV does not induce immune suppression in mast cell deficient mice. Conventional wisdom suggests mast cell migrate to sites of inflammation where they release a variety of immune modulatory mediators that affect immune function. We observed that UV radiation activates mast cell migration from the site of inflammation (skin) to the draining lymph nodes. When this "reverse mast cell migration" was inhibited by blocking CXCR4 binding to its ligand CXCL12, an interaction known to induce mast cell migration, immune suppression was ablated. This suggests that unconventional mast cell migration from the skin to the lymph nodes is critically important for the induction of immune suppression and sunlight-induced skin carcinogenesis. The goal of the experiments outlined in this proposal is to test this hypothesis. Four specific aims will be examined to provide data to support the hypothesis. Specific Aim #1 will focus on providing additional data to support the hypothesis that the migration of dermal mast cells from the skin to the draining lymph node is an essential step in the activation of immune suppression. Specific Aim #2 will focus on determining the mechanisms responsible for reverse mast cell migration. Specific Aim #3 will focus on determining how mast cells mediate immune suppression in the lymph nodes. Specific Aim #4 will examine the role of mast cells in UV-induced skin cancer induction. The long-term goal of my research is to determine the mechanism(s) underlying UV-induced immune suppression in order to provide insights in the development of new therapeutic reagents for skin cancer. Targeting mast cell migration may provide a new therapeutic target to prevent sunlight-induced skin cancer. In addition, preliminary data generated in my lab indicates that the immune suppression induced by treating the skin with other immunosuppressants (psoralen plus UVA and/or the dermal application of jet fuel) is mast cell dependent and activates reverse mast cell migration. This suggests that the data generated during the course of this proposal may have broad implications in regard to the mechanisms by which environmental immunosuppressants interact with the immune system to down-regulate its function. PUBLIC HEALTH RELEVANCE: The primary agent responsible for inducing skin cancer, the most prevalent form of human cancer, is the ultraviolet (UV) radiation in sunlight. UV radiation is also immune suppressive, and a variety of studies have shown that the immune suppression induced by sunlight is a major risk factor for skin cancer induction. The long term goal of my research is to gain a better understanding of the mechanisms underlying UV-induced immune suppression and skin cancer induction in order to develop new and novel therapeutic agents to prevent sunlight-induced skin cancer induction.

描述（由申请人提供）：紫外线（UV）辐射是主要的环境致癌物，也是非黑色素瘤皮肤癌的主要原因。紫外线辐射也是免疫抑制作用，紫外线暴露引起的全身免疫抑制是皮肤癌诱导的主要危险因素。我实验室的先前发现表明，紫外线暴露激活了细胞因子级联反应（紫外线？由于肥大细胞释放了许多已知的因素在紫外线诱导的系统性免疫抑制中发挥作用，因此我们专注于它们在诱导免疫抑制的作用，以更好地了解所涉及的机制。肥大细胞在紫外线诱导的免疫抑制中显然起着至关重要的作用，因为紫外线不会诱导肥大细胞缺乏小鼠的免疫抑制。传统的智慧表明，肥大细胞迁移到炎症部位，它们释放了影响免疫功能的各种免疫调节介质。我们观察到，紫外线辐射激活肥大细胞从炎症部位（皮肤）迁移到排水淋巴结。当这种“反向肥大细胞迁移”通过阻止CXCR4与其配体CXCL12结合时，这种相互作用已知诱导肥大细胞迁移的相互作用，则消融了免疫抑制。这表明非常规肥大细胞从皮肤迁移到淋巴结对于诱导免疫抑制和阳光诱导的皮肤致癌至关重要。该提案中概述的实验的目的是检验该假设。将检查四个具体目标以提供数据以支持该假设。具体目标＃1将集中于提供其他数据，以支持以下假设：皮肤肥大细胞从皮肤到排水淋巴结的迁移是激活免疫抑制的重要步骤。具体目标＃2将集中于确定负责反向肥大细胞迁移的机制。特定目标＃3将集中于确定肥大细胞如何介导淋巴结中的免疫抑制。特定的目标＃4将检查肥大细胞在紫外线诱导的皮肤癌诱导中的作用。我的研究的长期目标是确定紫外线诱导的免疫抑制的基本机制，以便在开发皮肤癌的新治疗试剂中提供见解。靶向肥大细胞迁移可能会提供一个新的治疗靶标，以防止阳光引起的皮肤癌。此外，在我的实验室中产生的初步数据表明，通过用其他免疫抑制剂（psoralen plus uva和/或喷气燃料的真皮施用）通过治疗皮肤引起的免疫抑制作用是肥大细胞的，并激活反向肥大细胞的迁移。这表明在本提案过程中生成的数据可能对环境免疫抑制剂与免疫系统相互作用以下调其功能的机制具有广泛的影响。 公共卫生相关性：负责诱发皮肤癌的主要药物是人类癌症的最普遍形式，是阳光中的紫外线（UV）辐射。紫外线辐射也是免疫抑制性的，许多研究表明，阳光诱导的免疫抑制是皮肤癌诱导的主要危险因素。我的研究的长期目标是更好地了解紫外线诱导的免疫抑制和皮肤癌诱导的机制，以开发新的和新颖的治疗剂，以防止阳光诱发的皮肤癌诱导。