Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Rheinish-Westphalian Technical University (RWTH) Aachen University, Aachen, Germany.
FASEB J. 2018 Aug;32(8):4428-4443. doi: 10.1096/fj.201800058R. Epub 2018 Mar 15.
The inflammatory cytokine macrophage migration-inhibitory factor (MIF) promotes atherosclerosis via lesional monocyte and T-cell recruitment. B cells have emerged as important components in atherogenesis, but the interaction between MIF and B cells in atherogenesis is unknown. Here, we investigated the atherosclerotic phenotype of Mif-gene deletion in Apoe mice. Apoe Mif mice fed a Western diet exhibited strongly reduced atherosclerotic lesions in brachiocephalic artery (BC) and abdominal aorta compared with controls. This phenotype was accompanied by reduced circulating B cells. Flow cytometry revealed a B-cell developmental defect with increased premature and immature B-cell counts in bone marrow (BM) of Apoe Mif mice and diminished B-cell numbers in spleen. This finding was linked with a decreased expression of Baff-R and differentiation-driving transcription factors at the immature B-cell stage, whereas peritoneal B cells exhibited unchanged CD80 and CD86 expression but vastly decreased CD9 and elevated CD23 levels, indicating that the developmental block favors the generation of immature, egressing, and reactive B cells. Mif deficiency did not affect absolute B-cell numbers in the vessel wall but favored a relative increase of B cells in the atheroprone BC region and the appearance of periadventitial B-cell-rich clusters. Of note, Mif mice exhibited a significant increase in oxidized low-density lipoprotein (oxLDL)-specific antibodies after the injection of oxLDL, indicating that Mif deficiency is associated with higher sensitivity of B cells against natural-occurring antigens such as oxLDL. Importantly, Apoe mice adoptively transplanted with ApoeMif BM showed reduced peripheral B cells compared with Apoe BM transplantation but no atheroprotection in the BC; also, whereas there was a selective increase in atheroprotective IgM-anti-oxLDL-antibodies in global Mif deficiency, BM-specific Mif deficiency also led to elevated proatherogenic anti-oxLDL-IgG. Together, these findings reveal a novel link between MIF and B cells in atherogenesis. Protection from atherosclerosis by Mif deficiency is associated with enhanced B-cell hypersensitivity, which in global but not BM-restricted Mif deficiency favors an atheroprotective autoantibody profile in atherosclerotic mice. Targeting MIF may induce protective B-cell responses in atherosclerosis.-Schmitz, C., Noels, H., El Bounkari, O., Straussfeld, E., Megens, R. T. A., Sternkopf, M., Alampour-Rajabi, S., Krammer, C., Tilstam, P. V., Gerdes, N., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.
炎症细胞因子巨噬细胞移动抑制因子 (MIF) 通过病变部位的单核细胞和 T 细胞募集促进动脉粥样硬化。B 细胞已成为动脉粥样硬化形成中的重要组成部分，但 MIF 和 B 细胞在动脉粥样硬化形成中的相互作用尚不清楚。在这里，我们研究了 Apoe 小鼠中 Mif 基因缺失的动脉粥样硬化表型。与对照组相比，喂食西方饮食的 Apoe Mif 小鼠的肱动脉 (BC) 和腹主动脉中的动脉粥样硬化病变明显减少。这种表型伴随着循环 B 细胞的减少。流式细胞术显示，Apoe Mif 小鼠骨髓 (BM) 中的 B 细胞发育缺陷，早期和不成熟 B 细胞计数增加，脾脏中的 B 细胞数量减少。这一发现与 Baff-R 的表达降低以及不成熟 B 细胞阶段的分化驱动转录因子有关，而腹膜 B 细胞的 CD80 和 CD86 表达不变，但 CD9 大大降低，CD23 水平升高，表明发育阻滞有利于不成熟、迁出和反应性 B 细胞的产生。Mif 缺乏不影响血管壁中绝对 B 细胞的数量，但有利于在易发生动脉粥样硬化的 BC 区域中 B 细胞的相对增加，并出现血管周围富含 B 细胞的簇。值得注意的是，Mif 小鼠在注射氧化低密度脂蛋白 (oxLDL) 后，oxLDL 特异性抗体显著增加，表明 Mif 缺乏与 B 细胞对天然存在的抗原（如 oxLDL）的敏感性增加有关。重要的是，与 Apoe BM 移植相比，接受 ApoeMif BM 移植的 Apoe 小鼠外周 B 细胞减少，但在 BC 中没有动脉粥样硬化保护；此外，在全局 Mif 缺乏中，存在选择性增加的抗动脉粥样硬化 IgM-抗 oxLDL-抗体，而 BM 特异性 Mif 缺乏也导致升高的促动脉粥样硬化抗 oxLDL-IgG。总之，这些发现揭示了 MIF 和动脉粥样硬化形成中的 B 细胞之间的新联系。Mif 缺乏对动脉粥样硬化的保护与 B 细胞超敏性增强有关，在全局而非 BM 受限的 Mif 缺乏中，有利于动脉粥样硬化小鼠中保护性自身抗体谱的形成。靶向 MIF 可能会在动脉粥样硬化中诱导保护性 B 细胞反应。
