Mechanisms of pericardial adipose tissue activation after myocardial infarction

急性心肌梗死（MI）是欧洲死亡率和发病率的主要原因。氧气和营养供应的缺乏导致大量心肌细胞坏死，从而诱导炎症反应。随后形成纤维性瘢痕和重塑过程，可能逐渐导致心脏功能受损和心力衰竭。过去研究心脏修复的潜在炎症机制和细胞关键参与者的研究主要集中在心脏内的细胞。然而，血管周围脂肪组织，特别是冠状动脉和心肌周围的脂肪组织在MI愈合和临床结局中的相关性迄今为止在很大程度上被忽视，基于我们先前的发现，即心包脂肪组织（PAT）包含MI后激活的免疫细胞簇，本项目的首要目的是阐明PAT如何感知心脏损伤，以及导致心包淋巴簇内免疫细胞活化的因素是什么。为了解决这个问题，我们将重点关注3个具体目标：（1）我们假设肾上腺素能神经控制心包FALC免疫细胞激活。(2)我们想弄清楚MI是否促进PAT内的淋巴管生成。与心包微血管接触的心包微血管有哪些特征？(3)我们进一步假设非经典单核细胞通过在其表面展示心脏抗原而作为抗原呈递细胞，从而促进心包淋巴细胞活化。此外，我们将研究我们最近发现的非经典单核细胞的特异性标志物（CD 274/PD-L1）是否可以在治疗上被阻断以改善MI后的心脏结局。这将通过研究遗传性非经典单核细胞缺乏对MI结局的影响来补充。我们的方法专注于心肌脂肪串扰，协调心脏损伤，修复和重塑过程，开辟了一个全新的概念。更好地了解心包免疫细胞激活的机制可能有助于开发新的治疗策略，以改善MI患者的临床结局。

Acute myocardial infarction (MI) is the leading cause of mortality and morbidity in Europe. The lack of oxygen and nutrient supply leads to necrosis of a large number of cardiomyocytes, which induces an inflammatory response. This is followed by the formation of a fibrous scar and remodeling processes that may progressively lead to impaired cardiac function and heart failure. Past research investigating the underlying inflammatory mechanisms and cellular key players of cardiac repair mainly focused on cells within the heart. However, the relevance of the perivascular adipose tissue, in particular the adipose tissue surrounding coronary arteries and myocardium in MI healing and clinical outcome has been largely neglected so far.Based on our previous discovery that pericardial adipose tissue (PAT) contains clusters of immune cells that are activated after MI, the overarching aim of this project is to clarify how the PAT senses cardiac injury, and what are the factors leading to immune cell activation within pericardial lymphoid clusters. To address this question, we will focus on 3 specific aims: (1) We hypothesize that adrenergic nerves control pericardial FALC immune cell activation. (2) We want to clarify whether MI promotes lymphangiogenesis within PAT. What are the characteristics of pericardial microvessels, which are in contact with pericardial FALCs? (3) We further hypothesize that non-classical monocytes serve as antigen presenting cells by displaying cardiac antigens on their surface, thereby contributing to pericardial lymphocyte activation. Moreover, we will investigate whether our recently identified specific marker for non-classical monocytes (CD274/PD-L1) can be therapeutically blocked to improve cardiac outcome after MI. This will be complemented by studying the impact of genetic non-classical monocyte deficiency on MI outcome.Our approach focusing on the myocardium-adipose crosstalk that orchestrates cardiac injury, repair and remodeling processes opens a completely novel concept. A better understanding of the mechanisms involved in pericardial immune cell activation may help developing new therapeutic strategies to improve the clinical outcome for MI patients.