Role and therapeutic targeting of TREM2 in monocyte/macrophage dependent ischemic heart repair

TREM2 在单核细胞/巨噬细胞依赖性缺血性心脏修复中的作用和治疗靶向

• 批准号: 458539578
• 负责人: Dr. Clement Cochain, Ph.D.
• 金额: --
• 依托单位: Institut für Experimentelle Biomedizin, Lehrstuhl II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/458539578?language=en
• 关键词: Role; therapeutic; targeting; TREM2; monocyte

Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction triggers the loss of non-regenerative cardiac tissue, inciting a wound healing process characterized by the formation of a fibrous scar, and gradual pathological remodeling of the heart leads to the transition to heart failure. Precisely understanding the mechanisms of cardiac repair is required to develop new therapeutic strategies for myocardial infarction patients. The inflammatory response that develops in the heart after ischemic injury is a major determinant of cardiac repair. In particular, circulating monocytes massively infiltrate the heart after infarction, where they differentiate into monocyte-derived macrophages with a dual role in cardiac repair, as they participate in inflammation-induced tissue damage but also perform functions necessary for tissue repair (such as dead cell removal, neovascularization). Thus, it is essential to identify mechanisms that promote monocyte/macrophage tissue repair capacities while taming their pathogenic functions. Recently, we mapped gene expression signatures of monocytes/macrophages in experimental myocardial infarction, and identified expression of the cell surface receptor TREM2 (Triggering Receptor Expressed on Myeloid cells-2) as a marker of monocytes/macrophages with a pro-tissue repair gene expression signature. The TREM2 pathway has been shown to be preferentially activated in macrophages in pathological contexts (e.g. neurodegeneration), attenuates macrophage pro-inflammatory activation, and drives macrophage functions such as phagocytosis or survival. We hypothesize that TREM2 controls monocyte/macrophage protective functions in the ischemic heart, and is a target for therapeutic immune modulation of ischemic heart repair. Using TREM2 deficient and loss-of-function mouse models, we will investigate the role of TREM2 in the monocyte response to myocardial infarction and analyze its role in monocyte production, phenotype and trafficking to the ischemic heart. We will furthermore analyze the role of TREM2 in monocyte differentiation into protective macrophages, and how these macrophages locally interact with other cardiac cell types to drive cardiac repair. Finally, we will test the hypothesis that activation of the TREM2 pathway with an anti-TREM2 activating antibody promotes monocyte/macrophage protective features and ameliorates cardiac repair. This project will provide an in-depth characterization of the role of TREM2 in monocyte/macrophage dependent cardiac repair, and proof of concept that TREM2 constitutes a therapeutic target for immune modulation of ischemic heart repair.

缺血性心脏病是全世界死亡的主要原因。心肌梗死触发不可再生心脏组织的丧失，引发以纤维瘢痕形成为特征的伤口愈合过程，心脏的逐渐病理性重塑导致心力衰竭的过渡。准确理解心脏修复的机制是制定新的治疗策略对心肌梗死患者的必要条件。缺血损伤后心脏发生的炎症反应是心脏修复的主要决定因素。特别是，循环单核细胞在梗死后大量浸润心脏，在那里它们分化为单核细胞来源的巨噬细胞，在心脏修复中起双重作用，因为它们参与炎症诱导的组织损伤，但也执行组织修复所需的功能（如死细胞去除，新生血管）。因此，有必要确定促进单核细胞/巨噬细胞组织修复能力的机制，同时驯服它们的致病功能。最近，我们绘制了实验性心肌梗死中单核/巨噬细胞的基因表达特征，并确定了细胞表面受体TREM2（髓系细胞上表达的触发受体-2）的表达作为单核/巨噬细胞具有促组织修复基因表达特征的标志物。TREM2通路已被证明在病理情况下（如神经退行性变）在巨噬细胞中优先激活，减弱巨噬细胞的促炎激活，并驱动巨噬细胞功能，如吞噬或存活。我们假设TREM2在缺血性心脏中控制单核细胞/巨噬细胞的保护功能，并且是缺血性心脏修复的治疗性免疫调节的靶点。利用TREM2缺陷和功能丧失小鼠模型，我们将研究TREM2在单核细胞对心肌梗死的反应中的作用，并分析其在单核细胞产生、表型和向缺血心脏转运中的作用。我们将进一步分析TREM2在单核细胞分化为保护性巨噬细胞中的作用，以及这些巨噬细胞如何与其他心脏细胞类型局部相互作用以驱动心脏修复。最后，我们将验证用抗TREM2激活抗体激活TREM2通路促进单核细胞/巨噬细胞保护功能并改善心脏修复的假设。该项目将深入表征TREM2在单核细胞/巨噬细胞依赖性心脏修复中的作用，并证明TREM2构成缺血性心脏修复免疫调节的治疗靶点的概念。