Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis
Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis
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DOI：
10.1182/blood-2010-07-298380
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发表时间：
2011-04-28
期刊：
影响因子：
20.3
通讯作者：
Du, Hong
中科院分区：
文献类型：
--
作者：
Qu, Peng;Yan, Cong;Du, Hong
基质金属蛋白酶12（MMP 12）是一种巨噬细胞分泌的蛋白酶。为了充分理解MMP 12在髓系细胞中的功能，建立了髓系特异性c-fms-rtTA/（TetO）（7）-CMV-MMP 12双转基因小鼠模型。在这种双转基因系统中，MMP 12的诱导异常地升高了骨髓（BM）中常见髓系祖细胞（CMP）和粒细胞/巨噬细胞祖细胞（GMP）群体的频率和数量，并且降低了巨核细胞/红细胞祖细胞（MEP）群体的频率和数量。在多个器官中，CD 11b（+）/Gr-1（+）未成熟细胞群全身性增加。体外和体内研究均显示，来自MMP 12过表达双转基因小鼠的CD 11b（+）/Gr-1（+）未成熟细胞对T细胞增殖和功能具有免疫抑制功能。MMP 12直接刺激谱系阴性（Lin（-））祖细胞分化为CD 11b（+）/Gr-1（+）未成熟细胞，这些未成熟细胞在体外对T细胞增殖和功能表现出免疫抑制。调节性T细胞（Tcells）增加。在肺中，IL-6的浓度增加，其异常激活致癌Stat 3并增加上皮肿瘤祖细胞中Stat 3下游基因的表达。MMP 12过度表达后依次发生自发性肺气肿和肺腺癌。骨髓嵌合体证实了MMP 12诱导的髓系细胞自主缺陷导致骨髓生成异常、免疫抑制和肺腺癌。（血。2011; 117（17）：4476-4489）
Matrix metalloproteinase 12 (MMP12) is a macrophage-secreting proteinase. To fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)(7)-CMV-MMP12 bitransgenic mouse model was created. In this bitransgenic system, induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) population in the bone marrow (BM). The CD11b(+)/Gr-1(+) immature cell population was systemically increased in multiple organs. Both in vitro and in vivo studies showed an immunosuppressive function on T-cell proliferation and function by CD11b(+)/Gr-1(+) immature cells from MMP12-overexpressing bitransgenic mice. MMP12 directly stimulated lineage-negative (Lin(-)) progenitor cells to differentiate into CD11b(+)/Gr-1(+) immature cells that showed immunosuppression on T-cell proliferation and function in vitro. Regulatory T cells (Tregs) were increased. In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. BM chimeras confirmed that the MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression, and lung adenocarcinoma. (Blood. 2011; 117(17): 4476-4489)