TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice
TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice
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DOI：
10.3324/haematol.2014.121590
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发表时间：
2015-08-01
期刊：
影响因子：
10.1
通讯作者：
Krueger, Achim
中科院分区：
文献类型：
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作者：
Kobuch, Julia;Cui, Haissi;Krueger, Achim
中性粒细胞的稳态可以影响包括癌症在内的多种炎症相关疾病的结果。这种体内平衡的调节机制尚未完全了解。我们之前发现，金属蛋白酶组织抑制剂-1 (TIMP-1) 的全身水平升高会导致肝脏中中性粒细胞的增加，从而强烈促进肝转移。在这里，我们报告增加全身 TIMP-1 水平足以诱导小鼠中性粒细胞增多。这并不是由于中性粒细胞存活时间延长或直接动员所致。然而，TIMP-1 诱导骨髓祖细胞富集，并伴随骨髓室中粒细胞生成相关基因的上调。 BrdU 脉冲标记证实增殖祖细胞是 TIMP-1 诱导的中性粒细胞增多的原因。 TIMP-1 变体将其蛋白酶抑制作用与其与细胞信号传导相关的 CD63 结合功能分开，揭示了 TIMP-1 信号传导结构域对于增强粒细胞生成是必要且充分的。因此，消除 TIMP-1 受体 CD63 会消除骨髓中的中性粒细胞增多和 TIMP-1 增强的粒细胞生成。我们的研究结果表明，TIMP-1 水平升高通过 CD63 信号传导影响中性粒细胞稳态。这可能提供与临床观察的联系，其中 TIMP-1 与炎症相关疾病的高严重性和不良预后相关。
The homeostasis of neutrophil granulocytes can affect the outcome of several inflammation-associated diseases including cancer. The regulation of this homeostasis is still not completely understood. We previously found that elevated systemic levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) induce an increase of neutrophils in the liver, which in turn strongly promotes liver metastasis. Here, we report that increasing systemic TIMP-1 levels were sufficient to induce neutrophilia in mice. This was not attributed to prolonged survival or direct mobilization of neutrophils. However, TIMP-1 induced enrichment of myeloid progenitors and concomitant upregulation of granulopoiesis-associated genes in the bone marrow compartment. BrdU pulse-labeling confirmed that proliferating progenitors accounted for TIMP-1-induced neutrophilia. TIMP-1 variants that dissect its protease-inhibitory from its CD63 binding function relevant for cell signaling revealed that the TIMP-1 signaling domain was necessary and sufficient to augment granulopoiesis. Consequently, ablation of the TIMP-1 receptor CD63 abolished both neutrophilia and TIMP-1-enhanced granulopoiesis in the bone marrow. Our findings reveal that elevated levels of TIMP-1 impact on neutrophil homeostasis via signaling through CD63. This may provide a link to clinical observations, where TIMP-1 correlates with high severity and bad prognosis in inflammation-associated diseases.