Regulation of immune cell function by the PVAT microenvironment

PVAT微环境对免疫细胞功能的调节

• 批准号: 10543524
• 负责人: Cheryl Elizabeth Rockwell
• 金额: $ 33.97万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-22 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543524
• 关键词: Adipose tissue; Adoptive Transfer; Adult; Animals; Automobile Driving; Blood Pressure; Blood Vessels; Buffers; CD8-Positive T-Lymphocytes; Cell Separation; Cell physiology; Cells; Cessation of life; Data; Development; Disease; Environment; Etiology; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Heart Diseases; High Fat Diet; High Prevalence; Homeostasis; Hypertension; Immune; Immune system; Immunity; Inbred Dahl Rats; Individual; Inflammation; Inflammatory; Interferon Type II; Interleukin-2; Knowledge; Ligands; Link; Mesentery; Modeling; Obesity; PPAR gamma; Patients; Peptide Hydrolases; Population; Prevalence; Production; Public Health; RNA Interference; Rattus; Refractory; Risk; Role; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; White Blood Cell Count procedure; cytokine; dietary control; hypertensive; immune function; immunoregulation; inflammatory milieu; inhibitor; insight; knock-down; novel; transcriptome sequencing

Project Summary – Project III Approximately 30% of U.S. adults have high blood pressure. Of particular concern, the prevalence of hypertension-related deaths increased 23% from 2000 to 2013, which correlates with a concurrent increase in the prevalence in obesity during this time. Adiposity increases an individual's risk for a number of diseases, including hypertension and heart disease. Accordingly, high fat diet-induced hypertension is currently a significant public health concern and a high priority. Thus, there is a critical need to elucidate the mechanisms driving the development of adiposity-associated hypertension. Our preliminary data demonstrate that there is a large immune cell population in perivascular adipose tissue and that there is a greater number of immune cells per mg tissue in PVAT as compared to other adipose tissues. Furthermore, our data also demonstrate that the PVAT microenvironment influences immune cell function. In particular, our results show mPVAT conditioned media from healthy rats suppresses IL-2 secretion by activated T cells, which suggests that under homeostatic conditions the PVAT microenvironment may serve to buffer T cell activation. Conversely, mPVAT conditioned media from rats on a HF diet promotes the production of pro-inflammatory cytokines, such as GM-CSF, IFNγ and IL-17a, by activated T cells. Notably, these effects are observed prior to the development of hypertension. RNA-sequencing of the PVAT from these rats revealed a substantial increase in the expression of DPP-4, a peptidase that acts as a costimulatory factor in T cells. We also found that DPP-4-specific inhibitors mitigated the increase in IL-17a by PVAT-CM from HF diet-fed rats. These exciting preliminary results have led to our central hypothesis that the PVAT microenvironment controls inflammation during homeostasis, while conversely promoting inflammation early during the development of high fat diet-induced hypertension. We propose to test this hypothesis through the following specific aims: 1. Determine the mechanism by which PVAT promotes a pro-inflammatory environment early during the development of HF diet-induced hypertension, while maintaining a semi-quiescent environment during health. We hypothesize that activation of PPARγ by endogenous ligands causes inhibition of IL-2 secretion during homeostasis, whereas induction of DPP-4 plays a role in promoting pro-inflammatory cytokine production during high fat diet-induced hypertension. and 2. Determine the role of CD4 and CD8 T cells in the development of HFD-induced hypertension and inflammation. We propose to perform T cell depletion in combination with adoptive transfers to determine the role of T cells in high fat diet-induced hypertension.

项目概要-项目三 大约30%的美国成年人患有高血压。特别令人关切的是， 从2000年到2013年，高血压相关死亡增加了23%，这与同时增加的 这段时间肥胖的流行率。肥胖增加了一个人患多种疾病的风险， 包括高血压和心脏病。因此，高脂肪饮食引起的高血压目前是一种 重大公共卫生问题和高度优先事项。因此，迫切需要阐明 推动肥胖相关高血压的发展。我们的初步数据表明，存在一个 在血管周围脂肪组织中存在大量免疫细胞群， 与其他脂肪组织相比，PVAT中的每mg组织。此外，我们的数据还表明， PVAT微环境影响免疫细胞功能。特别是，我们的研究结果表明，mPVAT条件 来自健康大鼠的培养基抑制活化的T细胞分泌IL-2，这表明在稳态下， 条件下，PVAT微环境可用于缓冲T细胞活化。相反，mPVAT条件 来自HF饮食大鼠的培养基促进促炎细胞因子如GM-CSF、IFNγ的产生 和IL-17 a。值得注意的是，这些影响在高血压发展之前就已观察到。 这些大鼠PVAT的RNA测序显示DPP-4的表达显著增加， 在T细胞中作为共刺激因子的肽酶。我们还发现DPP-4特异性抑制剂减轻了 通过PVAT-CM从HF饮食喂养的大鼠增加IL-17 a。这些令人兴奋的初步结果使我们 中心假设PVAT微环境在稳态期间控制炎症，而 相反地，在高脂肪饮食诱发的高血压的发展过程中促进早期炎症。我们 建议通过以下具体目标来检验这一假设：1.确定一种机制， PVAT在HF饮食诱导的发展早期促进促炎环境 高血压，同时在健康期间保持半静止的环境。我们假设激活 内源性配体对PPARγ的诱导可抑制IL-2的分泌，而内源性配体对IL-2的诱导可抑制IL-2的分泌。 DPP-4在高脂饮食诱导的炎症过程中促进促炎细胞因子的产生 高血压和2.确定CD 4和CD 8 T细胞在HFD诱导的T细胞免疫缺陷形成中的作用。 高血压和炎症。我们建议结合过继转移进行T细胞耗竭 以确定T细胞在高脂饮食诱导的高血压中的作用。