Soh Serena Ying, Faveeuw Christelle, Thiam Chung Hwee, Khoo Lawrence Han Boon, Yeo Kim Pin, Lim Sheau Yng, Lim Hwee Ying, Ng Jun Xiang, Angeli Veronique
Department of Microbiology, Immunology Programme, Life Science Institute, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, 59800 Lille, France.
J Immunol. 2016 Nov 15;197(10):3894-3904. doi: 10.4049/jimmunol.1500999. Epub 2016 Oct 21.
Recently, the role of B cells in atherosclerosis has gained more attention but studies have mainly focused on B1 and follicular B cell subsets. Therefore, the contribution of marginal zone (MZ) B cells in experimental atherosclerosis remains elusive. In the current study, we examined the MZ B cell compartment in atherosclerotic apoE-deficient (apoE) mice and found that hypercholesterolemia in these mice was associated with an increased number and percentage of MZ B cells. This aberrant accumulation of MZ B cells was not associated with alterations in their development or increased proliferation but was due to decreased apoptotic cell death. This decrease in MZ B cell death in apoE mice was associated with the reduced capacity of invariant NKT (iNKT) cells to produce IFN-γ and IL-4 after activation. Lowering cholesterol plasma levels with ezetimibe in apoE mice reversed iNKT function and MZ B cell accumulation. To elucidate the mechanism whereby iNKT cells control MZ B cell accumulation in apoE mice, we performed an adoptive transfer of iNKT cells and found that only wild-type iNKT cells but not IFN-γ iNKT cells reversed MZ B cell accumulation in apoE recipient mice. Our findings reveal that lipid changes associated with atherosclerotic disease induce decreased production of IFN-γ by iNKT, which in turn leads to aberrant accumulation of MZ B cells. This study further extends the importance of iNKT cells in regulating MZ B cell compartment.
最近，B细胞在动脉粥样硬化中的作用受到了更多关注，但研究主要集中在B1细胞和滤泡B细胞亚群上。因此，边缘区（MZ）B细胞在实验性动脉粥样硬化中的作用仍不清楚。在本研究中，我们检测了动脉粥样硬化载脂蛋白E缺陷（apoE）小鼠的MZ B细胞区室，发现这些小鼠的高胆固醇血症与MZ B细胞数量和百分比增加有关。MZ B细胞的这种异常积累与其发育改变或增殖增加无关，而是由于凋亡性细胞死亡减少。apoE小鼠中MZ B细胞死亡的减少与不变自然杀伤T（iNKT）细胞激活后产生干扰素-γ（IFN-γ）和白细胞介素-4（IL-4）的能力降低有关。用依泽替米贝降低apoE小鼠的血浆胆固醇水平可恢复iNKT功能和MZ B细胞积累。为了阐明iNKT细胞控制apoE小鼠中MZ B细胞积累的机制，我们进行了iNKT细胞的过继转移，发现只有野生型iNKT细胞而不是IFN-γ iNKT细胞能逆转apoE受体小鼠中MZ B细胞的积累。我们的研究结果表明，与动脉粥样硬化疾病相关的脂质变化会导致iNKT产生的IFN-γ减少，进而导致MZ B细胞异常积累。这项研究进一步扩展了iNKT细胞在调节MZ B细胞区室中的重要性。
