Myeloid-derived suppressor cells accumulate among myeloid cells contributing to tumor growth in matrix metalloproteinase 12 knockout mice
Myeloid-derived suppressor cells accumulate among myeloid cells contributing to tumor growth in matrix metalloproteinase 12 knockout mice
复制标题
骨髓源性抑制细胞在骨髓细胞中积聚，促进基质金属蛋白酶 12 敲除小鼠的肿瘤生长
DOI：
10.1016/j.cellimm.2017.12.006
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发表时间：
2018-05-01
影响因子：
4.3
通讯作者：
Wang, Lijing
中科院分区：
文献类型：
--
作者：
Li, Jiangchao;Zhang, Xiaohan;Wang, Lijing
髓系来源的抑制细胞(MDSCs)常见于患者和荷瘤小鼠，其来源为未成熟的髓系细胞。在健康人中，未成熟的髓样细胞在骨髓中形成，分化为树突状细胞、巨噬细胞和中性粒细胞。然而，目前尚不清楚某些基因缺失是否会导致MDSCs在未携带肿瘤的小鼠体内积聚。在这里，我们观察到基质金属蛋白酶12基因敲除小鼠(MMP12(-/-)小鼠)和野生型小鼠(MMP12(+/+)小鼠)的骨髓中MDSCs聚集。CD4(+)细胞数量显著减少，调节性T细胞上调，检测MDSCs功能。结果提示，MMP12(-/-)转基因小鼠的免疫监视功能受损。静脉注射B16黑色素瘤细胞后，MMP12(-/-)小鼠比MMP12(+/+)小鼠出现更多的转移性肺结节。同时，与MMP12(+/+)小鼠相比，MMP12(-/-)小鼠的肿瘤中出现了更多的MDSCs。从机制上讲，我们进行了MDSC阻断试验，发现阻断MDSC导致MMP12(-/-)小鼠肿瘤生长减少。此外，我们还证实了MMP12(-/-)小鼠的巨噬细胞在骨髓中大量分泌IL-1β，从而诱导MDSCs在骨髓中聚集。综上所述，这些结果表明MMP12(-/-)小鼠的巨噬细胞可以通过IL-1β与髓系细胞发生串扰，诱导MDSCs聚集，从而促进肿瘤的生长。它揭示了巨噬细胞在髓系细胞分化中的关键作用。
Myeloid-derived suppressor cells (MDSCs) are found frequently in patients and mice bearing tumors, which derived from immature myeloid cells. In healthy individuals, immature myeloid cells formed in the bone marrow differentiating to dendritic cells, macrophages and neutrophils. However, it is unclear whether some gene deficiency will lead to MDSCs accumulation in mice without bearing tumor. Here, we observed that MDSCs accumulated in the bone marrow of matrix metalloproteinase 12 knockout mice (MMP12(-/-) mice) compared with wild type mice (MMP12(+/+) mice). And the number of CD4(+) cells dramatically decreased, regulatory T cells was up-regulation and MDSCs function were determined. The results suggested that immune surveillance have been impaired in MMP12(-/-) transgenic mice. After intravenous administration of B16 murine melanoma cells, MMP12(-/-) mice developed more metastatic pulmonary nodules than MMP12(+/+) mice. Meanwhile, more MDSCs appeared in the tumors of MMP12(-/-) mice compared with those of MMP12(+/+) mice. Mechanistically, we performed a MDSC blocking assay, finding that blockade of MDSCs resulted in reducing growth of tumors in MMP12(-/-) mice. Furthermore, we ascertained that macrophages in MMP12(-/-) mice abundantly secrete IL-1 beta in bone marrow which induce the accumulation of MDSCs in the bone marrow. Together, these results demonstrated that the macrophages in MMP12(-/-) mice could crosstalk with myeloid cells through IL-1 beta, inducing MDSCs accumulation, then contributing to tumor growth. It has revealed that the critical roles of macrophage in myeloid cells differentiation.