Regulation of immune cell function by the PVAT microenvironment

项目摘要--项目III 大约30%的美国成年人患有高血压。特别令人关注的是， 从2000年到2013年，与高血压相关的死亡人数增加了23%，这与同时增加的 在此期间肥胖症的流行情况。肥胖会增加个人患多种疾病的风险， 包括高血压和心脏病。因此，高脂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，迫切需要阐明这些机制。 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有大量的免疫细胞，并且有更多的免疫细胞 PVAT中的每毫克组织与其他脂肪组织相比。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是有条件的 健康大鼠的培养液抑制激活的T细胞分泌IL-2，这表明在体内平衡的情况下 PVAT微环境可能起到缓冲T细胞活化的作用。相反，mPVAT条件 HF饮食大鼠的培养基能促进促炎细胞因子的产生，如GM-csf、干扰素γ 和IL-17a，通过激活的T细胞。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，a，a的表达显著增加 在T细胞中起协同刺激因子作用的多肽酶。我们还发现，DPP-4特异性抑制剂可以缓解 PVAT-CM对HF饮食大鼠IL-17a水平的影响。这些令人兴奋的初步结果导致了我们的 核心假设是PVAT微环境在动态平衡期间控制炎症，而 相反，在高脂饮食诱导的高血压发展过程中，早期就会促进炎症。我们 建议通过以下具体目标来检验这一假设：1.确定 PVAT在饮食诱导的HF形成早期促进促炎环境 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的抑制在动态平衡过程中抑制IL-2的分泌，而诱导 DPP-4在高脂饮食诱导的促炎细胞因子产生中的作用 高血压。2.确定CD4和CD8 T细胞在HFD诱导的发病过程中的作用 高血压和炎症。我们建议在接受移植的同时进行T细胞耗竭 探讨T细胞在高脂饮食诱导的高血压中的作用。

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.