Role of Trem1 in ultraviolet radiation-induced immune suppression

紫外线B（UVB）辐射（290-320 nm）除了诱导突变外，还引起免疫抑制 细胞只有在免疫抑制环境中存在突变细胞时，肿瘤才会发生。器官 接受免疫抑制药物治疗的移植受者的风险大大增加（高达100 倍）的紫外线诱导的皮肤癌和肿瘤的发展行为更具侵略性。在美国， 从1992年到2012年，皮肤癌的发病率翻了一番。每年有超过350万新病例被诊断出来。 皮肤癌的流行是一个重大的公共卫生问题，也是医疗保健系统的巨大成本 在美国和全世界。因此，深入了解UVB诱导的免疫损伤的发病机制是非常必要的 并制定新的预防和治疗战略。我们的初步数据显示， 增加小鼠和人皮肤组织中髓样细胞（Trem）-1上表达的触发受体， 来自小鼠皮肤和引流淋巴结的部分CD 11b+细胞。重要的是，我们第一次 证明用拮抗剂肽阻断Trem 1抑制UVB诱导的免疫抑制。 此外，阻断Trem 1抑制UVB诱导的皮肤癌发生。研究结果显示， Trem 1在UVB诱导的免疫抑制和皮肤癌发生中的作用尚未被认识。而且有 常见的概念是UVB诱导的致耐受性抗原呈递细胞（APC）是诱导免疫耐受所必需的。 免疫抑制尽管在人类和动物研究中有强有力的证据表明CD 11b+细胞含有 致耐受性APC、CD 11b+细胞是异质的，并且特异性致耐受性APC仍有待鉴定。我们的数据 显示UVB通过常规树突状细胞2型（cDC 2）细胞新亚群诱导Trem 1表达 （CD11b+）。UVB诱导的引流淋巴结中的Trem 1 + cDC 2细胞表达高水平的免疫原性。 抑制分子CD 200和PD-L1，在正常小鼠中几乎检测不到。这些发现定义了新的 Trem 1 + cDC 2细胞，并暗示Trem 1介导的免疫抑制的新机制。它形成了一个强大的 我们假设UVB诱导的Trem 1 + cDC 2是负责UVB诱导的耐受性APC的前提。 免疫抑制和皮肤癌发生。靶向Trem 1 + cDC 2细胞具有翻译潜力， 预防和治疗UVB诱发的致癌作用。基于新的发现，拟议的研究将检查 动物和人类的假设。目的1：鉴定UVB诱导的Trem 1 + cDC 2细胞是否为特异性耐受原细胞 APC和确定其免疫抑制活性的机制。目标2将确定 UVB诱导的Trem 1 + cDC 2细胞的发育。目的3：检测UVB对人Trem 1 + cDC 2细胞的诱导作用 皮肤和血液，并确定它们在免疫抑制中的作用。总的来说，当前的应用程序将适用于 先进的技术，并使用遗传和药理学方法来充分表征Trem 1 + cDC 2细胞 探讨UVB诱导免疫抑制的新机制。其结果将影响到 研究领域，并可能利用新的战略，预防和治疗皮肤癌。

Ultraviolet B (UVB) radiation (290-320 nm) causes immune suppression, in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. Organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of UV induced skin cancers and the tumors that do develop behave more aggressively. In the United States, the incidence of skin cancer has doubled from 1992 to 2012. Over 3.5 million new cases are diagnosed each year. The epidemic of skin cancer represents a major public health issue and is a tremendous cost to healthcare systems in the United States and worldwide. It is highly desired to understand the pathogenesis of UVB induced immune suppression and develop new strategies for prevention and treatment. Our preliminary data show that UVB increases Triggering receptor expressed on myeloid cells (Trem)-1 in mouse and human skin tissues and by a portion of CD11b+ cells from the mouse skin and draining lymph nodes. Importantly, we have, for the first time demonstrated that blocking Trem1 with an antagonist peptide inhibits UVB induced immune suppression. Moreover, blocking Trem1 inhibits UVB induced cutaneous carcinogenesis. The findings reveal a previously unrecognized role of Trem1 in UVB induced immune suppression and skin carcinogenesis. Furthermore, a common concept is that UVB induced tolerogenic antigen presenting cells (APC) are required for the induction of immune suppression. Although strong evidence in human and animal studies indicates that CD11b+ cells contain tolerogenic APC, CD11b+ cells are heterogeneous and specific tolerogenic APC remain to be identified. Our data show that UVB induces Trem1 expression by a novel subset of conventional dendritic cell type 2 (cDC2) cells (CD11b+). The UVB induced Trem1+ cDC2 cells in the draining lymph nodes express high levels of immune inhibitory molecules CD200 and PD-L1 and are hardly detectable in normal mice. These findings define novel Trem1+ cDC2 cells and implicate novel mechanisms for Trem1 mediated immune suppression. It forms a strong premise for our hypothesis that UVB induced Trem1+ cDC2 are tolerogenic APC responsible for UVB induced immune suppression and skin carcinogenesis. Targeting Trem1+ cDC2 cells has translational potentials for the prevention and treatment of UVB induced carcinogenesis. Based on the novel findings, proposed studies will examine the hypothesis in animals and humans. Aim 1 will identify UVB induced Trem1+ cDC2 cells as specific tolerogenic APC and determine mechanisms for their immune suppressive activity. Aim 2 will determine mechanisms for the development of UVB induced Trem1+ cDC2 cells. Aim 3 will determine UVB induced Trem1+ cDC2 cells in human skin and blood and determine their roles in immune suppression. Collectively, the current application will apply advanced technology and use genetic and pharmacological approaches to fully characterize the Trem1+ cDC2 cells and explore new mechanisms for UVB induced immune suppression. The outcome will have impacts in the research field and may be exploited to new strategies for prevention and treatment of skin cancers.