Efferocytosis-Directed Inflammation Resolution and Repair in the Hypoxic Heart

Thorp Project Summary Abstract. 急性心肌梗死（AMI）后的心力衰竭是发病的重要原因， mortality.尽管药理学的进步已经显著降低了死亡率， AMI后心力衰竭的风险正在增加。这迫使新的发展 保护损伤后心脏组织完整性的方法。组织损伤的程度 在急性心肌梗死的急性期， 导致心脏功能受损的重塑。因此，一个重要的目标是 最大限度地减少梗死面积及其扩大，这是心肌细胞死亡的函数， 无效的组织修复。通过吞噬作用有效地吞噬死亡心肌细胞， 这对开始解决炎症和心脏愈合至关重要。例如减少 垂死心肌细胞的红细胞增多与发病率增加直接相关， AMI后死亡率。最近的研究还表明，巨噬细胞亚群的差异， 负责心脏的吞噬和修复功能。在细胞水平之外， 心肌吞噬细胞内调节细胞毒性的分子途径 心脏的炎症消退，仍然未知。索普实验室已经制造出 最近发现，红细胞增多信号通路的适应不良失活使心脏恶化， 心肌梗死后的修复，为一类新的分子靶点铺平了道路，以促进心脏愈合。 我们的研究新揭示了TAM家族的凋亡细胞受体MerTK和AXL， 令人惊讶地通过不同机制调节心肌细胞胞浆细胞增多， 心肌炎症消退。我们在非基因靶向小鼠和人类中的数据也 表明AXL在AMI期间通过蛋白水解而被自然抑制。这些初步发现导致 重要的新的调查路线。这包括：（一）AXL独特的程度 在巨噬细胞中发挥作用，调节缺氧心脏中的AMI修复，包括这可能是如何 被开发用于治疗干预。(II)新的TAM受体依赖性和非依赖性 免疫代谢机制的红细胞增多症和炎症的解决和（III）的 在小鼠和患者中AMI后AXL蛋白水解的因果作用未知。因此，这些新目标 准备在仍然相对欠研究的过程中取得重大进展， 心脏巨噬细胞，巨噬细胞免疫代谢信号传导和TAM的基础生物学 受体。新创造的工具，包括新的基因工程实验动物，将 有助于严格测试上述原则，并对心脏 炎症和更广泛的组织损伤原理。

Thorp Project Summary Abstract-Resubmission. Heart failure after acute myocardial infarction (AMI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post AMI-induced heart failure is increasing. This compels the development of new approaches to preserve the integrigty of cardiac tissue after injury. The extent of tissue damage in the acute phase of AMI is a critical determinant of the degree of subsequent adverse remodeling that leads to impaired cardiac performance. As such, an important goal is to minimize infarct size and its expansion, which are a function of cardiomyocyte death and ineffecient tissue repair. Efficient phagocytic removal of dying cardiomyocytes by efferocytosis is critical to initiating resolving inflammation and to heart healing. For example, reduced efferocytosis of dying cardiomyocytes is directly correlated with increased morbidity and mortality post AMI. Recent studies have also shown macrophage subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes that regulate efferocytosis-directed inflammation resolution in the heart, remain unknown. The Thorp laboratory has made the recent discovery that maladaptive inactivation of efferocytosis signaling pathways worsen heart repair after AMI, paving the way for a new class of molecular targets to enhance heart healing. Our studies newly reveal that the apoptotic cell receptors of the TAM family, MerTK and AXL, surprisingly act though distinct mechanisms to regulate cardiomyocyte efferocytosis and myocardial inflammation resolution. Our data in non-gene targeted mice and humans also suggest that AXL is naturally inhibited during AMI by proteolysis. These initial findings led to important new lines of investigation. This includes: (I) The degree to which AXL uniquely functions in macrophages to regulate AMI repair in the hypoxic heart, including how this may be exploited for thereapeutic intervention. (II) Novel TAM receptor-dependent and -independent immunometabolic mechanisms of efferocytosis and inflammation resolution and (III) the unknown causal role of AXL proteolysis post AMI in mice and patients. Thus, these new Aims are poised to make significant advances in the still relatively understudied process of efferocytosis in heart, efferocytic immunometabolic signaling, and the basic biology of TAM receptors. Newly created tools, including novel gene-engineered experimental animals, will assist in rigorous testing of the aforementioned principles and are of significance to both cardiac inflammation and broader principles of tissue injury.