Kumar Dhananjay, Pandit Rajan, Yurdagul Arif
Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA.
Immunometabolism (Cobham). 2023 Jan 23;5(1):e00017. doi: 10.1097/IN9.0000000000000017. eCollection 2023 Jan.
Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Rupture-prone atheromas that give rise to myocardial infarction and stroke are characterized by the presence of a necrotic core and a thin fibrous cap. During homeostasis, cellular debris and apoptotic cells are cleared quickly through a process termed "efferocytosis". However, clearance of apoptotic cells is significantly compromised in many chronic inflammatory diseases, including atherosclerosis. Emerging evidence suggests that impairments in efferocytosis drive necrotic core formation and contribute significantly to plaque vulnerability. Recently, it has been appreciated that successive rounds of efferocytosis, termed "continual efferocytosis", is mechanistically distinct from single efferocytosis and relies heavily on the metabolism and handling of apoptotic cell-derived cargo. In vivo, selective defects in continual efferocytosis drive secondary necrosis, impair inflammation resolution, and worsen atherosclerosis. This Mini Review focuses on our current understanding of the cellular and molecular mechanisms of continual efferocytosis and how dysregulations in this process mediate nonresolving inflammation. We will also discuss possible strategies to enhance efferocytosis when it fails.
动脉粥样硬化性心血管疾病是全球主要的死亡原因。易破裂的动脉粥样硬化斑块可引发心肌梗死和中风，其特征是存在坏死核心和薄纤维帽。在稳态过程中，细胞碎片和凋亡细胞通过一个称为“胞葬作用”的过程迅速清除。然而，在包括动脉粥样硬化在内的许多慢性炎症性疾病中，凋亡细胞的清除明显受损。新出现的证据表明，胞葬作用受损会驱动坏死核心的形成，并显著增加斑块的易损性。最近，人们认识到连续几轮的胞葬作用，即“持续胞葬作用”，在机制上不同于单次胞葬作用，并且严重依赖于凋亡细胞衍生货物的代谢和处理。在体内，持续胞葬作用的选择性缺陷会导致继发性坏死，损害炎症消退，并加重动脉粥样硬化。本综述聚焦于我们目前对持续胞葬作用的细胞和分子机制的理解，以及该过程中的失调如何介导炎症持续不消退。我们还将讨论在胞葬作用失败时增强其作用的可能策略。
