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 III 大约 30% 的美国成年人患有高血压。特别值得关注的是， 从 2000 年到 2013 年，高血压相关死亡人数增加了 23%，这与同时发生的高血压相关死亡人数的增加有关。 这段时间肥胖症的流行。肥胖会增加个体患多种疾病的风险， 包括高血压和心脏病。因此，目前高脂饮食诱发的高血压是 重大公共卫生问题和高度优先事项。因此，迫切需要阐明其机制 推动肥胖相关高血压的发展。我们的初步数据表明，有一个 血管周围脂肪组织中存在大量免疫细胞，并且存在更多数量的免疫细胞 与其他脂肪组织相比，PVAT 中每毫克组织的含量。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，我们的结果显示 mPVAT 条件 来自健康大鼠的培养基抑制活化 T 细胞分泌 IL-2，这表明在稳态条件下 PVAT 微环境可以起到缓冲 T 细胞激活的作用。相反，mPVAT 条件 HF 饮食大鼠的培养基促进促炎细胞因子的产生，例如 GM-CSF、IFNγ 和 IL-17a，由激活的 T 细胞产生。值得注意的是，这些影响是在高血压发生之前观察到的。 对这些大鼠的 PVAT 进行 RNA 测序显示 DPP-4 的表达显着增加，DPP-4 是一种 肽酶在 T 细胞中充当共刺激因子。我们还发现 DPP-4 特异性抑制剂可减轻 PVAT-CM 使 HF 饮食喂养的大鼠 IL-17a 增加。这些令人兴奋的初步结果使我们 中心假设是 PVAT 微环境在稳态过程中控制炎症，而 相反，在高脂肪饮食诱发的高血压发展过程中早期会促进炎症。我们 建议通过以下具体目标来检验这一假设： 1. 确定机制 PVAT 在 HF 饮食诱导的发展早期促进促炎环境 高血压，同时保持健康期间的半静止环境。我们假设激活 内源性配体对 PPARγ 的作用会导致体内平衡过程中 IL-2 分泌的抑制，而诱导 DPP-4 在高脂肪饮食诱导的促炎细胞因子产生中发挥作用 高血压。 2.确定CD4和CD8 T细胞在HFD诱导的发育中的作用 高血压和炎症。我们建议结合过继转移进行 T 细胞清除 确定 T 细胞在高脂肪饮食诱发的高血压中的作用。