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

• 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
• 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

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）发育。但是，心脏机理 HF发育过程中的炎症解决方案仍然鲜为人知。程序性细胞死亡蛋白1（PD1） 是一种通过抑制初始T细胞诱导和通过 保持T细胞耐受性。 PD1阻断抗体用于癌症治疗，但该治疗也导致 某些患者的心脏毒性。我们发现PD1 KO或PD1阻断抗体极大地加剧了 横向主动脉收缩（TAC）诱导的心脏感染，HF和死亡，表明PD1执行更多 在压力条件下的重要作用。要了解心脏感染中PD1抑制的机制，我们 在假或TAC后，研究果定的心脏免疫细胞和来自野生型和PD1 KO小鼠的血管内皮细胞 通过将单细胞Cuit-seq与条形码抗体一起用于膜蛋白标记。使用单细胞 引用seq，我们还研究了来自HF小鼠和假小鼠的肺免疫球。生物信息学分析具有 提供了这些细胞的大量信息 - 显示了细胞簇的急剧变化，富集的途径 先天和适应性免疫调查以及各种免疫细胞亚群中代谢途径的变化 HF小鼠，或TAC后的PD1 KO。 GDT细胞（T细胞的一个子集）可以分为IL-17（GDT17）或IFNG 生产者。肺部免疫细胞的引用seq表明，HF引起了各种T细胞的急剧变化， 巨噬细胞簇，TH17和GDT17细胞中PD1的急剧增加，这表明PD1导出了一个重要的 在抑制Th17和GDT17细胞以及HF进展中的作用。心脏免疫细胞中的Cite-seq TAC后，PD1 KO小鼠中CD8+ T细胞和GDT细胞的浸润增加，这些浸润的细胞是 IFNG+细胞，表明CD8+ T细胞，GDT细胞和IFNG可能有助于恶化的心脏 PD1 KO小鼠的炎症。基于这些令人兴奋的发现，我们假设TAC引起的心脏和 肺部炎症分辨率由PD1通过保守和独特的途径调节 分别由CD8+ T细胞，GDT细胞和TH17产生的IFNG和IL17部分控制。增强 我们对PD1在心脏感染和HF中作用的研究的创新性严格，我们还将研究CD8 细胞特异性PD1 KO小鼠。 AIM-1。检验IFNG和CD8+ T细胞有助于恶化的假设 TAC后，PD1 KO中的心脏感染，细胞因子风暴和HF。在Additon中，我们将确定PD1是否 CD8+ T细胞中的KO足以加剧TAC诱导的心脏注射和HF。 AIM-2。确定 IL17和GDT细胞在促进TAC诱导的心脏感染和HF中的作用和潜在机制 PD1抑制后。该申请对特殊利益通知的响应高度响应，而不是ES-ES-20-018作为 拟议的研究将提高我们对心脏和肺中PD1和T细胞机制的理解 炎症分辨率，以及在心脏和肺免疫细胞簇中配置和独特的变化 HF的发展和进展。