亲炎性M1巨噬细胞在动脉粥样硬化的进展中起着关键作用。Par3-Like蛋白(Par3L)是Par3家族的同源物，参与细胞极性的建立。已有研究表明，Par3L能维持乳腺干细胞的干性，促进结直肠癌细胞的存活。本研究中，我们探讨了极性蛋白Par3L在M1巨噬细胞极化和动脉粥样硬化中的作用。为了诱导动脉粥样硬化，使用Apoe-/-小鼠喂养动脉粥样硬化西方饮食8周或16周。我们发现Par3L在人类和小鼠的动脉粥样硬化斑块中表达显著增加。在小鼠的原代巨噬细胞中，氧化低密度脂蛋白（oxLDL，50 μg/mL）的时间依赖性地增加了Par3L的表达。在Apoe-/-小鼠中，通过腺病毒介导的Par3L过表达加重了动脉粥样硬化斑块形成，伴随着动脉粥样硬化斑块和骨髓中M1巨噬细胞的增加。在小鼠骨髓源性巨噬细胞(BMDMs)和腹腔巨噬细胞(PMs)中，我们发现Par3L过表达通过激活p65和ERK信号通路而不是p38和JNK信号通路促进了LPS和IFNγ诱导的M1巨噬细胞极化。我们的研究结果揭示了Par3L作为极性蛋白在加重动脉粥样硬化和促进M1巨噬细胞极化中的一个前所未知的角色，提示Par3L有可能成为动脉粥样硬化的潜在治疗靶点。© 2023. 作者（们）专属许可给中国科学院上海药物研究所和中国药理学会。

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 μg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.