Mechanism of PD1 on cardiac inflammation resolution during heart failure development

PD1 在心力衰竭发展过程中解决心脏炎症的机制

基本信息

批准号：
10557113
负责人：
YINGJIE CHEN
金额：
$ 58.13万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557113
关键词：
Antibodies Attenuated Bar Codes Bioinformatics Blocking Antibodies CD8-Positive T-Lymphocytes Cardiac Cardiotoxicity Cardiovascular Diseases Cardiovascular system Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Development Failure Genes Genomics Heart failure IL17 gene IL1R1 gene Immune Immune response Infiltration Inflammation Investigation Knockout Mice Label Left Lung Macrophage Mediating Membrane Proteins Metabolic Pathway Mus Myocarditis Pathway interactions Patients Play Production Proteins Pulmonary Hypertension Pulmonary Inflammation Resolution Role Signal Transduction Stress T cell infiltration T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Vascular Endothelial Cell adaptive immune response aorta constriction cancer therapy cytokine release syndrome experimental study heart cell innovation interest programmed cell death protein 1 right ventricular failure sham surgery targeted cancer therapy

项目摘要

Cardiovascular inflammation promotes Heart failure (HF) development. However, mechanism of cardiac inflammation resolution during HF development is still poorly understood. Programmed cell death protein 1 (PD1) is a protein that keeps the body’s immune responses in check, both by inhibiting initial T cell induction and by maintaining T cell tolerance. PD1 blocking antibodies are used in cancer treatment, but the treatment also leads to cardiac toxicity in some patients. We found that PD1 KO or PD1 blocking antibodies dramatically exacerbated transverse aortic constriction (TAC)-induced cardiac inflammation, HF, and death, indicating PD1 exerts a more important role under stress conditions. To understand mechanisms of PD1 inhibition in cardiac inflammation, we studied cardiac immune cells and vascular endothelial cells from wild type and PD1 KO mice after sham or TAC by using single-cell CITE-seq together with barcoded antibodies for membrane protein labeling. Using single-cell CITE-seq, we also studied lung immune cells from HF mice and sham mice. Bioinformatics analyses have provided enormously information of these cells – showing dramatic alterations of cell clusters, enriched pathways of innate & adaptive immune responses, and changes of metabolic pathways in various immune cell subsets in HF mice, or in PD1 KO after TAC. gdT cells (a subset of T cells) can be divided into either IL-17 (gdT17) or IFNg producers. CITE-seq of lung immune cells showed that HF caused dramatic changes of various T cell and macrophage clusters, a dramatic increase of PD1 in Th17 and gdT17 cells, suggesting PD1 exerts an important role in suppressing Th17, and gdT17 cells as well as HF progression. CITE-seq in cardiac immune cells showed that infiltration of CD8+ T cells and gdT cells increased in PD1 KO mice after TAC, and these infiltrated cells are IFNg+ cells, indicating that CD8+ T cells, gdT cells, and IFNg may contribute to the exacerbated cardiac inflammation in PD1 KO mice. Based on these exciting findings, we hypothesize that TAC-induced cardiac and pulmonary inflammation resolution is regulated by PD1 through both conserved and unique pathways at least partially controlled by IFNg and IL17 produced by CD8+ T cells, gdT cells, and Th17, respectively. To enhance the innovative rigor of our investigation of the role of PD1 in cardiac inflammation and HF, we will also study CD8 cell specific PD1 KO mice. Aim-1. Test the hypothesis that IFNg and CD8+ T cells contribute to the exacerbated cardiac inflammation, cytokine storm, and HF in PD1 KO after TAC. In additon, we will determine whether PD1 KO in CD8+ T cells is sufficient to exacerbate TAC-induced cardiac inflammation and HF. Aim-2. Determine the roles and underlying mechanisms of IL17 and gdT cells in promoting TAC-induced cardiac inflammation and HF after PD1 inhibition. This application is highly responsive to the Notice of Special Interest NOT-ES-20-018 as the proposed studies will advance our understanding of the mechanisms of PD1 and T cells in cardiac and lung inflammation resolution, and the conserved & unique changes in cardiac and lung immune cell clusters during HF development and progression.

心血管炎症促进心力衰竭（HF）的发展然而，心脏的机制。心力衰竭发展过程中的炎症消退仍知之甚少。是一种蛋白质，通过抑制初始 T 细胞诱导和通过维持T细胞耐受性PD1阻断抗体用于癌症治疗，但治疗也导致我们发现PD1 KO或PD1阻断抗体会严重加剧一些患者的心脏毒性。横主动脉缩窄 (TAC) 诱发的心脏炎症、心力衰竭和死亡，表明 PD1 发挥更大的作用为了了解 PD1 抑制在心脏炎症中的重要作用，我们研究了假手术或 TAC 后野生型和 PD1 KO 小鼠的心脏免疫细胞和血管内皮细胞通过使用单细胞 CITE-seq 与条形码抗体一起进行膜蛋白标记。 CITE-seq，我们还研究了 HF 小鼠和假小鼠的肺免疫细胞，并进行了生物信息学分析。提供了这些细胞的大量信息——显示细胞簇的巨大变化、丰富的途径先天性和适应性免疫反应的变化，以及各种免疫细胞亚群代谢途径的变化 HF 小鼠或 TAC 后的 PD1 KO 中的 gdT 细胞（T 细胞的一个子集）可分为 IL-17 (gdT17) 或 IFNg。肺部免疫细胞的CITE-seq显示，HF引起各种T细胞和细胞的巨大变化。巨噬细胞簇中，Th17 和 gdT17 细胞中 PD1 急剧增加，表明 PD1 发挥重要作用 CITE-seq 在抑制 Th17 和 gdT17 细胞以及心脏免疫细胞中的 HF 进展中发挥作用。 TAC 后 PD1 KO 小鼠中 CD8+ T 细胞和 gdT 细胞的浸润增加，这些浸润细胞 IFNg+细胞，表明CD8+T细胞、gdT细胞和IFNg可能导致心脏恶化基于这些令人兴奋的发现，我们探究了 TAC 诱导的心脏和炎症。 PD1 至少通过保守且独特的途径调节肺部炎症的消退分别由 CD8+ T 细胞、gdT 细胞和 Th17 产生的 IFNg 和 IL17 部分控制来增强。除了我们研究 PD1 在心脏炎症和心力衰竭中的作用之外，我们还将研究 CD8 细胞特异性 PD1 KO 小鼠测试 IFNg 和 CD8+ T 细胞导致病情加重的假设。 TAC 后 PD1 KO 中的心脏炎症、细胞因子风暴和 HF 另外，我们将确定 PD1 是否存在。 CD8+ T 细胞中的 KO 足以加剧 TAC 诱导的心脏炎症和 HF。 IL17和gdT细胞在促进TAC诱导的心脏炎症和心力衰竭中的作用和潜在机制 PD1 抑制后，该应用程序对特别关注通知 NOT-ES-20-018 高度敏感。拟议的研究将增进我们对心脏和肺中 PD1 和 T 细胞机制的理解炎症消退，以及心脏和肺免疫细胞簇的保守且独特的变化心力衰竭的发生和进展。