Impaired B Cell Inhibition by Lupus Bone Marrow Mesenchymal Stem Cells Is Caused by Reduced CCL2 Expression
Impaired B Cell Inhibition by Lupus Bone Marrow Mesenchymal Stem Cells Is Caused by Reduced CCL2 Expression
复制标题
CCL2 表达减少导致狼疮骨髓间充质干细胞对 B 细胞的抑制受损
DOI：
10.4049/jimmunol.1400036
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发表时间：
2014-11-15
影响因子：
4.4
通讯作者：
Sun, Lingyun
中科院分区：
文献类型：
--
作者：
Che, Nan;Li, Xia;Sun, Lingyun
来自健康人和正常小鼠的间充质干细胞（MSC）在体外可以抑制正常B细胞的增殖、分化和抗体分泌。然而，它仍然是未知的，是否从狼疮样小鼠和系统性红斑狼疮（SLE）患者的MSC表现出相同的免疫调节活性的正常MSC的B细胞抑制，如果没有，潜在的分子机制是什么。在这项研究中，我们发现，从狼疮样小鼠和SLE患者骨髓来源的MSC在抑制正常B细胞增殖和分化方面存在缺陷，这是由CCL 2水平降低引起的。正常MSC中CCL 2的敲低损害了它们对B细胞的抑制能力。相反，在狼疮MSC中CCL 2的过表达恢复了它们在体外对B细胞的免疫调节能力，并且在体内改善了MRL/lpr小鼠中狼疮肾炎的病理学和血清学变化。从机制上讲，MSC介导的B细胞抑制依赖于CCL 2的基质金属蛋白酶蛋白水解加工。这些发现揭示了CCL 2在MSC调节B细胞中的新功能，并表明CCL 2对MSC的操纵可能作为开发更有效的基于MSC的治疗与B细胞活化相关的自身免疫性疾病（如SLE）的潜在途径。
Mesenchymal stem cells (MSC) from healthy human and normal mice can inhibit normal B cell proliferation, differentiation, and Ab secretion in vitro. However, it remains unknown whether MSC from lupus-like mice and patients with systemic lupus erythematosus (SLE) exhibit the same immunoregulatory activity as normal MSC for B cell inhibition and, if not, what the underlying molecular mechanism would be. In this study, we showed that bone marrow–derived MSCs from lupus-like mice and SLE patients had an impairment in suppressing normal B cell proliferation and differentiation, which was caused by the reduction of CCL2 levels. Knockdown of CCL2 in normal MSC damaged their suppressive capacity for B cells. Conversely, overexpression of CCL2 in lupus MSCs restored their immunoregulatory ability for B cells in vitro and ameliorated the pathology of lupus nephritis and serological changes in MRL/lpr mice in vivo. Mechanistically, MSC-mediated B cell inhibition was dependent on matrix metalloproteinase proteolytic processing of CCL2. These findings reveal a novel function of CCL2 in B cell regulation by MSCs and suggest that CCL2 manipulation on MSCs may serve as a potential pathway for developing the more effective MSC-based therapy in autoimmune diseases associated with B cell activation, such as SLE.