Abstract：
Lymphatic dysfunction is a pivotal pathological mechanism underlying the development of early atherosclerotic plaques. Potential targets of lymphatic function must be identified to realize the early prevention and treatment of atherosclerosis (AS). The immunity-related GTPase Irgm1 is involved in orchestrating cellular autophagy and apoptosis. However, the effect of Irgm1 on early AS progression, particularly through alterations in lymphatic function, remains unclear. In this study, we confirmed the protective effect of lymphangiogenesis on early-AS in vivo. Subsequently, an in vivo model of early AS mice with Irgm1 knockdown shows that Irgm1 reduces early atherosclerotic plaque burden by promoting lymphangiogenesis. Given that lymphatic endothelial cell (LEC) autophagy significantly contributes to lymphangiogenesis, Irgm1 may enhance lymphatic circulation by promoting LEC autophagy. Moreover, Irgm1 orchestrates autophagy in LECs by inhibiting mTOR and facilitating nuclear translocation of Tfeb. Collectively, these processes lead to lymphangiogenesis. Thus, this study establishes a link between Irgm1 and early AS, thus revealing a novel mechanism by which Irgm1 exerts an early protective influence on AS within the context of lymphatic circulation. The insights gained from this study have the potential to revolutionize the approach and management of AS onset.
摘要：
淋巴管功能障碍是早期动脉粥样硬化斑块形成的重要病理机制。必须确定淋巴功能的潜在靶标，以实现动脉粥样硬化（AS）的早期预防和治疗。免疫相关的GTPaseIrgm1参与协调细胞自噬和凋亡。然而,Irgm1对早期AS进展的影响，特别是通过改变淋巴功能，尚不清楚。在这项研究中,我们证实了体内淋巴管生成对早期AS的保护作用。随后，具有Irgm1敲低的早期AS小鼠体内模型显示Irgm1通过促进淋巴管生成减少早期动脉粥样硬化斑块负荷。鉴于淋巴内皮细胞（LEC）自噬显著促进淋巴管生成，Irgm1可能通过促进LEC自噬来增强淋巴循环。此外，Irgm1通过抑制mTOR和促进Tfeb的核易位来协调LECs中的自噬。总的来说，这些过程导致淋巴管生成。因此，这项研究建立了Irgm1和早期AS之间的联系，从而揭示了Irgm1在淋巴循环背景下对AS产生早期保护性影响的新机制。从这项研究中获得的见解有可能彻底改变AS发病的方法和管理。
