Regulation of immune cell function by the PVAT microenvironment

点击翻译按钮获取中文摘要

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.