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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：
10345497
负责人：
YINGJIE CHEN
金额：
$ 57.47万
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/10345497
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 Interleukin-17 Investigation Knockout Mice Label Left Lung Mediating Membrane Proteins Metabolic Pathway Mus Myocarditis Pathway interactions Patients Play Production Proteins Pulmonary Hypertension Pulmonary Inflammation Resolution Role Signal Transduction Stress T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Tumor-infiltrating immune cells Vascular Endothelial Cell adaptive immune response base cancer therapy constriction cytokine release syndrome experimental study heart cell innovation interest macrophage programmed cell death protein 1 pulmonary function 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，心脏的机制在HF发展过程中的炎症消退仍然知之甚少。程序性细胞死亡蛋白1（PD 1）是一种蛋白质，通过抑制初始T细胞诱导和抑制免疫反应，维持T细胞耐受性。PD 1阻断抗体用于癌症治疗，但治疗也导致心脏毒性的可能性我们发现PD 1 KO或PD 1阻断抗体显著加剧了横主动脉缩窄（TAC）诱导的心脏炎症，HF和死亡，表明PD 1发挥了更大的作用。压力条件下的重要作用。为了了解心脏炎症中PD 1抑制的机制，我们研究了假手术或TAC后野生型和PD 1 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与条形码抗体一起用于膜蛋白标记。使用单细胞 CITE-seq，我们还研究了来自HF小鼠和假手术小鼠的肺免疫细胞。生物信息学分析提供了这些细胞的大量信息-显示了细胞簇的巨大变化，丰富了通路先天性和适应性免疫反应，以及各种免疫细胞亚群中代谢途径的变化， HF小鼠中，或在TAC后的PD 1 KO中。gdT细胞（T细胞的亚群）可分为IL-17（gdT 17）或IFNg 生产商肺免疫细胞的CITE-seq显示，HF引起各种T细胞的显著变化，在Th 17和gdT 17细胞中，PD 1显著增加，表明PD 1发挥重要作用。在抑制Th 17和gdT 17细胞以及HF进展中的作用。心脏免疫细胞中的CITE-seq显示在TAC后PD 1 KO小鼠中CD 8 + T细胞和gdT细胞的浸润增加，并且这些浸润的细胞是 IFNg+细胞，表明CD 8 + T细胞，gdT细胞和IFNg可能有助于加重的心脏病。在PD 1 KO小鼠中的炎症。基于这些令人兴奋的发现，我们假设TAC诱导的心脏和肺部炎症消退至少通过保守和独特的途径由PD 1调节，分别由CD 8 + T细胞、gdT细胞和Th 17产生的IFNg和IL 17部分控制。加强我们对PD 1在心脏炎症和HF中的作用的研究具有创新的严谨性，我们还将研究CD 8 细胞特异性PD 1 KO小鼠。目标一测试IFNg和CD 8 + T细胞有助于加重的免疫缺陷的假设。心脏炎症、细胞因子风暴和TAC后PD 1 KO中的HF。此外，我们将确定PD 1是否 ⑶ 8 + T细胞中的KO足以加重TAC诱导的心脏炎症和HF。目标二确定 IL 17和gdT细胞在TAC诱导的心脏炎症和HF中的作用及其机制 PD 1抑制后。本申请高度响应特别关注通知NOT-ES-20-018，提出的研究将促进我们对心脏和肺中PD 1和T细胞机制的理解，炎症消退，以及心脏和肺免疫细胞簇在治疗过程中的保守和独特变化。 HF发展和进展。