The hypoxic environment reprograms the cytokine/chemokine expression profile of human mature dendritic cells
The hypoxic environment reprograms the cytokine/chemokine expression profile of human mature dendritic cells
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DOI：
10.1016/j.imbio.2012.02.002
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发表时间：
2013-01-01
期刊：
影响因子：
2.8
通讯作者：
Bosco, Maria Carla
中科院分区：
文献类型：
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作者：
Blengio, Fabiola;Raggi, Federica;Bosco, Maria Carla
髓样树突状细胞 (DC) 是专业的抗原呈递细胞，对于协调免疫和维持自我耐受至关重要。 DC 的发育和功能受到组织微环境中存在的复杂的抑制和激活信号网络的严格调节，DC 反应失调可能导致炎症放大、耐受性丧失或免疫逃逸机制的建立。在低氧分压 (pO(2)) 的条件下，在病理部位募集的单核细胞前体产生成熟 (m)DC。然而，低氧微环境调节这些细胞功能的方式仍不清楚。我们证明，慢性缺氧（4天，1％O-2）会促进原代人单核细胞产生的mDC中高度促炎基因表达谱的发生，其特征是编码促炎趋化因子/细胞因子和/或其受体的一组重要基因的调节。在趋化因子系统内，编码中性粒细胞趋化蛋白的基因强烈上调，例如 CXCL2、CXCL3、CXCL5、CXCL6 和 CXCL8，以及激活/记忆 T 淋巴细胞、单核细胞和未成熟 (i) DC 细胞，例如 CXCL2、CXCL3、CXCL5、CXCL6 和 CXCL8。观察到 CCL20、CCL3 和 CCL5，同时编码幼稚/静息 T 细胞趋化剂、CCL18 和 CCL23 的基因表达降低。其他缺氧诱导基因编码在炎症和血管生成中起主要作用的细胞因子，包括骨桥蛋白、血管内皮生长因子和 IL-1 β。 mRNA 调节与蛋白质分泌并行。这些结果表明，O-2 可用性减少的条件通过调整细胞因子/趋化因子库，将 mDC 重新编程为促炎方向，从而影响它们在病理部位调节白细胞运输和激活的能力，对慢性炎症疾病的发病机制具有潜在影响。 (C) 2012 年爱思唯尔有限公司。版权所有。
Myeloid dendritic cells (DCs) are professional antigen-presenting cells critical for the orchestration of immunity and maintenance of self-tolerance. DC development and functions are tightly regulated by a complex network of inhibitory and activating signals present in the tissue microenvironment, and dysregulated DC responses may result in amplification of inflammation, loss of tolerance, or establishment of immune escape mechanisms. Generation of mature (m)DCs from monocytic precursors recruited at pathological sites occurs under condition of low partial oxygen pressure (pO(2)). However, the way in which the hypoxic microenvironment modulates the functions of these cells is still not clear. We demonstrate that chronic hypoxia (4 days, 1% O-2) promotes the onset of a highly proinflammatory gene expression profile in mDCs generated from primary human monocytes, characterized by the modulation of a significant cluster of genes coding for proinflammatory chemokines/cytokines and/or their receptors. Within the chemokine system, strong upregulation of genes encoding proteins chemotactic for neutrophils, such as CXCL2, CXCL3, CXCL5, CXCL6, and CXCL8, and for activated/memory T lymphocytes, monocytes, and immature (i) DCs, e.g. CCL20, CCL3 and CCL5, was observed, concomitant with decreased expression of genes coding for naive/resting T cells chemoattractants, CCL18 and CCL23. Other hypoxia-inducible genes coded for cytokines with a primary role in inflammation and angiogenesis, including osteopontin, vascular endothelial growth factor, and IL-1 beta. mRNA modulation was paralleled by protein secretion. These results suggest that conditions of reduced O-2 availability reprograms mDCs toward a proinflammatory direction by tuning the cytokine/chemokine repertoire, thus affecting their ability to regulate leukocyte trafficking and activation at pathological sites, with potential implications for the pathogenesis of chronic inflammatory diseases. (C) 2012 Elsevier GmbH. All rights reserved.