Abstract
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.
Highlights
Hypoxia results from the imbalance between cellular oxygen supply and consumption and is a characteristic feature of many physiological and pathological circumstances, such as inflammation, tumor and blastocyst implantation[1,2,3]
We reported that hypoxia (1% O2) altered human monocyte-derived dendritic cells (DCs) to a DC2 phenotype by LPS maturation and hypoxia-DCs skewed polarization of T cells toward a Th2 phenotype[12]; the mechanisms accounting for this were not clear
The mean fluorescence intensity of CD44 increased up to approximately 2 folds in mature DCs (mDCs) cultured under hypoxia (Fig. 1c), which was further corroborated by the result from Enzyme-linked immunosorbent assay (ELISA) that the soluble-form of CD44 in the supernatant of hypoxic DCs was significantly reduced (Fig. 1d)
Summary
Hypoxia results from the imbalance between cellular oxygen supply and consumption and is a characteristic feature of many physiological and pathological circumstances, such as inflammation, tumor and blastocyst implantation[1,2,3]. DCs are a heterogeneous family of professional antigen presenting cells (APCs) involved in the initiation of immunity They infiltrate into the lesions in inflammatory diseases and some solid tumors, playing an important role in the initiation, polarization and termination of the adaptive immunity[4]. Wiesner C et al reported that another kinesin family protein KIF3 played an important role in MT1-MMP surface exposure and extracellular matrix degradation in macrophages[31]. Our results indicated that the KIF2A/MT1-MMP/CD44 axis impelled hypoxic DCs to mediate Th2 polarization from naïve T cells. These data implicated a fundamental mechanism controlling the Th1/Th2 differentiation under hypoxia condition via DCs
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