Yang Meixiang, Liu Yanguo, Ren Guangwen, Shao Qianqian, Gao Wenjuan, Sun Jintang, Wang Huayang, Ji Chunyan, Li Xingang, Zhang Yun, Qu Xun
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Department of Medical Oncology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Sci Rep. 2015 Sep 1;5:13674. doi: 10.1038/srep13674.
A low partial oxygen pressure (hypoxia) occurs in many pathological environments, such as solid tumors and inflammatory lesions. Understanding the cellular response to hypoxic stress has broad implications for human diseases. As we previously reported, hypoxia significantly altered dendritic cells (DCs) to a DC2 phenotype and promoted a Th2 polarization of naïve T cells with increased IL-4 production. However, the underlying mechanisms still remain largely unknown. In this study, we found the over-expression of surface CD44 in DCs was involved in this process via ligand binding. Further investigation showed hypoxia could reduce the surface expression of membrane type 1 metalloprotease (MT1-MMP) via down-regulating the kinesin-like protein KIF2A, which subsequently alleviated the shedding of CD44 from DCs. Moreover, KIF2A expression was found negatively regulated by HIF-1α in hypoxic microenvironment. These results suggest a previously uncharacterized mechanism by which hypoxia regulates the function of DCs via KIF2A/MT1-MMP/CD44 axis, providing critical information to understand the immune response under hypoxia.
低氧分压（缺氧）存在于许多病理环境中，如实体瘤和炎症性病变。了解细胞对缺氧应激的反应对人类疾病具有广泛的意义。正如我们之前报道的，缺氧显著地将树突状细胞（DCs）转变为DC2表型，并通过增加白细胞介素-4的产生促进幼稚T细胞向Th2极化。然而，其潜在机制在很大程度上仍然未知。在本研究中，我们发现DCs表面CD44的过表达通过配体结合参与了这一过程。进一步研究表明，缺氧可通过下调驱动蛋白样蛋白KIF2A来降低膜型1金属蛋白酶（MT1-MMP）的表面表达，进而减轻CD44从DCs上的脱落。此外，发现在缺氧微环境中KIF2A的表达受缺氧诱导因子-1α负调控。这些结果提示了一种以前未被描述的机制，即缺氧通过KIF2A/MT1-MMP/CD44轴调节DCs的功能，为理解缺氧条件下的免疫反应提供了关键信息。
