Suur Bianca E, Karadimou Glykeria, Willems Colin J J M, Bergman Otto, Lengquist Mariette, Kronqvist Malin, Baumgartner Roland, Malin Stephen, Gisterå Anton, Hansson Göran K, Mälarstig Anders, Hedin Ulf, Ketelhuth Daniel F J, Matic Ljubica
Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden.
Vascul Pharmacol. 2025 Jun;159:107490. doi: 10.1016/j.vph.2025.107490. Epub 2025 Mar 15.
Proprotein convertase subtilisins/kexins (PCSKs) have been implicated in cancers and cardiovascular disease. We have shown that PCSK6 is a key protease regulating smooth muscle cell (SMC)-mediated vascular remodeling, but also that it can be expressed by T cells and macrophages in atherosclerotic plaques. Whether PCSK6 regulates innate and adaptive immune responses in the context of vascular inflammation is still unknown.
In this study, detailed immunophenotyping of constitutive Pcsk6 mice was performed. Bone marrow transplantation into high-cholesterol diet fed Ldlr mice was used to investigate PCSK6-mediated immune effects in atherogenesis and plaque stability.
Compared to controls, Pcsk6 mice showed higher plasma levels of the chemoattractants CCL2 and CCCL3, and Th17 cytokines IL-17 A and IL-17F. Pcsk6 ablation led to increased naïve and effector-memory CD4+ and CD8+ cell numbers in the spleen, and increased release of IL-17 A, IFN-γ and IL-10 as well as proliferation by spleenocytes in vitro. Lack of Pcsk6 also affected innate immunity as macrophages from Pcsk6 mice secreted more cytokines, including TNF-α, CCL2, IL-6 and IL-10 upon LPS stimulation in vitro, and were more prone to oxLDL uptake. In line with a pro-inflammatory phenotype, Pcsk6➔Ldlr transplanted mice presented a higher atherosclerotic plaque burden compared to Ldlr receiving control bone marrow. Although larger, Pcsk6➔Ldlr plaques showed increased stability features, including collagen deposition and SMC presence coinciding with significantly increased local levels of the fibrogenic cytokine IL-17.
Global Pcsk6 ablation leads to the activation of both adaptive and innate immune systems. Interestingly, Pcsk6 ablation in bone marrow of hyperlipidemic mice revealed its dual role in atherogenesis, activating a Th17-SMC modulatory axis that promotes plaque stability, despite increased atherosclerotic burden.
前蛋白转化酶枯草杆菌蛋白酶/kexin（PCSKs）与癌症和心血管疾病有关。我们已经表明，PCSK6是调节平滑肌细胞（SMC）介导的血管重塑的关键蛋白酶，而且它也可以在动脉粥样硬化斑块中的T细胞和巨噬细胞中表达。在血管炎症的背景下，PCSK6是否调节先天性和适应性免疫反应仍然未知。
在本研究中，对组成型Pcsk6小鼠进行了详细的免疫表型分析。将骨髓移植到喂食高胆固醇饮食的Ldlr小鼠中，以研究PCSK6在动脉粥样硬化发生和斑块稳定性中的免疫作用。
与对照组相比，Pcsk6小鼠血浆中的趋化因子CCL2和CCCL3以及Th17细胞因子IL-17A和IL-17F水平更高。Pcsk6基因敲除导致脾脏中幼稚和效应记忆CD4+和CD8+细胞数量增加，以及IL-17A、IFN-γ和IL-10的释放增加，以及体外脾细胞的增殖。Pcsk6的缺失也影响先天性免疫，因为来自Pcsk6小鼠的巨噬细胞在体外LPS刺激后分泌更多细胞因子，包括TNF-α、CCL2、IL-6和IL-10，并且更容易摄取氧化型低密度脂蛋白（oxLDL）。与促炎表型一致，Pcsk6→Ldlr移植小鼠与接受对照骨髓的Ldlr小鼠相比，动脉粥样硬化斑块负担更高。尽管Pcsk6→Ldlr斑块更大，但显示出稳定性特征增加，包括胶原沉积和SMC存在，同时局部促纤维化细胞因子IL-17水平显著增加。
全身性Pcsk6基因敲除导致适应性和先天性免疫系统的激活。有趣的是，高脂血症小鼠骨髓中的Pcsk6基因敲除揭示了其在动脉粥样硬化发生中的双重作用，激活了促进斑块稳定性的Th17-SMC调节轴，尽管动脉粥样硬化负担增加。
