Induction of CD36 and thrombospondin-1 in macrophages by hypoxia-inducible factor 1 and its relevance in the inflammatory process.
Induction of CD36 and thrombospondin-1 in macrophages by hypoxia-inducible factor 1 and its relevance in the inflammatory process.
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DOI：
10.1371/journal.pone.0048535
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Barrachina MD
中科院分区：
文献类型：
--
作者：
Ortiz-Masià D;Díez I;Calatayud S;Hernández C;Cosín-Roger J;Hinojosa J;Esplugues JV;Barrachina MD
炎症是血管组织对病原体或受损细胞的复杂生物反应的一部分。首先，炎性细胞试图去除有害的刺激，然后是主要由衰老细胞的吞噬作用介导的愈合过程。缺氧和p38-MAPK与炎症相关，并且在炎症组织中检测到缺氧诱导因子1（HIF-1）。我们的目的是分析p38-MAPK和HIF-1在巨噬细胞中CD 36（一种B类清道夫受体）及其配体血小板反应蛋白（TSP-1）的转录调节中的作用，并评估该途径在凋亡中性粒细胞吞噬作用中的参与。我们还评估了炎症性肠病患者粘膜中HIF-1α、p38-MAPK和CD 36的免疫染色。结果表明，缺氧增加了巨噬细胞对中性粒细胞的吞噬作用，并诱导了CD 36和TSP-1的表达。加入p38-MAPK抑制剂显著降低了由缺氧引起的CD 36和TSP-1表达的增加，并降低了巨噬细胞中HIF-1α的稳定性。用miHIF-1α-靶向载体瞬时转染巨噬细胞，阻断了缺氧期间CD 36和TSP-1 mRNA表达的增加，并降低了吞噬作用，从而突出了HIF-1转录活性的作用。CD 36和TSP-1是必要的嗜中性粒细胞的吞噬诱导缺氧巨噬细胞，因为这些蛋白质的功能阻断破坏了这一过程。免疫组化结果显示，炎症性肠病患者肠黏膜中有CD 36、HIF-1α和p38-MAPK的表达。损伤粘膜固有层细胞中HIF-1α和CD 36的表达与CD 36和p38-MAPK的表达呈正相关。我们的研究结果表明，HIF-1依赖的上调CD 36和TSP-1介导的增加吞噬中性粒细胞的巨噬细胞在缺氧期间。此外，他们认为炎症性肠病患者受损粘膜中的CD 36表达取决于p38-MAPK和HIF-1活性。
Inflammation is part of a complex biological response of vascular tissue to pathogens or damaged cells. First inflammatory cells attempt to remove the injurious stimuli and this is followed by a healing process mediated principally by phagocytosis of senescent cells. Hypoxia and p38-MAPK are associated with inflammation, and hypoxia inducible factor 1 (HIF-1) has been detected in inflamed tissues. We aimed to analyse the role of p38-MAPK and HIF-1 in the transcriptional regulation of CD36, a class B scavenger receptor, and its ligand thrombospondin (TSP-1) in macrophages and to evaluate the involvement of this pathway in phagocytosis of apoptotic neutrophils. We have also assessed HIF-1α, p38-MAPK and CD36 immunostaining in the mucosa of patients with inflammatory bowel disease. Results show that hypoxia increases neutrophil phagocytosis by macrophages and induces the expression of CD36 and TSP-1. Addition of a p38-MAPK inhibitor significantly reduced the increase in CD36 and TSP-1 expression provoked by hypoxia and decreased HIF-1α stabilization in macrophages. Transient transfection of macrophages with a miHIF-1α-targeting vector blocked the increase in mRNA expression of CD36 and TSP-1 during hypoxia and reduced phagocytosis, thus highlighting a role for the transcriptional activity of HIF-1. CD36 and TSP-1 were necessary for the phagocytosis of neutrophils induced by hypoxic macrophages, since functional blockade of these proteins undermined this process. Immunohistochemical studies revealed CD36, HIF-1α and p38-MAPK expression in the mucosa of patients with inflammatory bowel disease. A positive and significant correlation between HIF-1α and CD36 expression and CD36 and p38-MAPK expression was observed in cells of the lamina propria of the damaged mucosa. Our results demonstrate a HIF-1-dependent up-regulation of CD36 and TSP-1 that mediates the increased phagocytosis of neutrophils by macrophages during hypoxia. Moreover, they suggest that CD36 expression in the damaged mucosa of patients with inflammatory bowel disease depends on p38-MAPK and HIF-1 activity.
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4.4
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