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.

项目摘要 - 项目III 大约30％的美国成年人患有高血压。特别关心的是 从2000年到2013年，与高血压相关的死亡人数增长了23％，这与同时增加 这段时间的肥胖症患病率。脂肪增加了个人患多种疾病的风险， 包括高血压和心脏病。可以肯定的是，高脂肪饮食引起的高血压目前是 重大的公共卫生关注和重点。这是阐明机制的迫切需要 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的大型免疫细胞种群，并且有更多的免疫细胞 与其他脂肪组织相比，PVAT中的每毫克组织。此外，我们的数据还表明 PVAT微环境会影响免疫电池功能。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的T细胞的IL-2分泌，这表明在体内稳态下 条件PVAT微环境可用于缓冲T细胞活化。相反，MPVAT条件 HF饮食中大鼠的培养基促进了促炎细胞因子的产生，例如GM-CSF，IFNγ 和IL-17A，通过活化的T细胞。值得注意的是，在高血压发展之前观察到这些影响。 来自这些大鼠的PVAT的RNA测序显示DPP-4的表达大幅增加 肽酶在T细胞中充当共刺激因子。我们还发现DPP-4特异性抑制剂缓解了 HF饮食喂养的大鼠PVAT-CM的IL-17A增加。这些令人兴奋的初步结果导致了我们的 中心假设是PVAT微环境控制着体内稳态期间的注射，而 相反，在高脂肪饮食引起的高血压的发展过程中早期促进炎症。我们 提出通过以下特定目的检验该假设的提议：1。确定其机制 PVAT在HF饮食引起的早期促进促炎环境 高血压，同时保持健康期间的半季度环境。我们假设激活 内源配体的PPARγ在稳态过程中引起IL-2分泌的抑制作用，而诱导 DPP-4在高脂饮食引起的促进促炎性细胞因子产生中起作用 高血压。和2。确定CD4和CD8 T细胞在HFD诱导的发展中的作用 高血压和炎症。我们建议将T细胞部署与自适应转移相结合 确定T细胞在高脂饮食诱导的高血压中的作用。