Increased expression of surface CD44 in hypoxia-DCs skews helper T cells toward a Th2 polarization.
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.
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Meixiang
M
Yang
Department of Medical Oncology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Yanguo
Y
Liu
Department of Molecular Biology, LTL255, Washington Road, Princeton University, Princeton, New Jersey 08544, USA.
Guangwen
G
Ren
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Qianqian
Q
Shao
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Wenjuan
W
Gao
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Jintang
J
Sun
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Huayang
H
Wang
Department of Hematology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Chunyan
C
Ji
Department of Neurosurgery, Key Laboratory of Neuro-Oncology and Immunology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Xingang
X
Li
The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
Yun
Y
Zhang
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Xun
X
Qu
D015687:Cell Hypoxia; D016764:Cell Polarity; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology
D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C509805:KIF2A protein, human; D034741:RNA, Small Interfering; D015847:Interleukin-4; D020781:Matrix Metalloproteinase 1; D016547:Kinesins