Heparin inhibits intracellular Mycobacterium tuberculosis bacterial replication by reducing iron levels in human macrophages.
Heparin inhibits intracellular Mycobacterium tuberculosis bacterial replication by reducing iron levels in human macrophages.
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DOI：
10.1038/s41598-018-25480-y
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发表时间：
2018-05-08
影响因子：
4.6
通讯作者：
Giri P
中科院分区：
文献类型：
--
作者：
Abreu R;Essler L;Loy A;Quinn F;Giri P
铁对哺乳动物及其相关病原体都是一种至关重要的微量营养素，大量文献表明，结核分枝杆菌（Mtb）被抑制，无法从宿主获取铁，从而严重减弱。相反，饮食铁浓度增加或血色素沉着症患者长期以来与更严重的结核病（TB）疾病结局相关。我们观察到，在巨噬细胞感染后，Mtb杆菌通过增加哺乳动物铁调节蛋白hepcidin的表达和下调铁输出蛋白铁转运蛋白（ferroportin）的表达，强烈促进细胞内铁的隔离。肝素是一种由肥大细胞和嗜碱性细胞在组织损伤部位释放的高度硫酸化的糖胺聚糖。在结核分枝杆菌感染期间，肝素改变肺泡上皮细胞的细胞内运输并减少肺外传播，但最近，肝素也被报道抑制肝细胞中hepcidin的表达，降低细胞内铁的可用性。在本报告中，我们证明肝素可显著降低Mtb杆菌感染的巨噬细胞中hepcidin的表达。与未处理的巨噬细胞相比，肝素处理的巨噬细胞具有更高的铁转运蛋白表达，促进铁输出并降低细胞内杆菌的铁可用性。因此，我们在这里描述了一种新的免疫调节作用和肝素对人巨噬细胞分枝杆菌感染的潜在治疗作用。
Iron is a crucial micronutrient for both mammals and their associated pathogens, and extensive literature has shown that Mycobacterium tuberculosis (Mtb) bacilli inhibited from acquiring iron from the host are severely attenuated. In contrast, increased dietary iron concentrations or patients with hemochromatosis have long been associated with a more severe tuberculosis (TB) disease outcome. We have observed that upon macrophage infection, Mtb bacilli strongly promote intracellular iron sequestration, both through increased expression of hepcidin, a key mammalian iron regulatory protein, and downregulation of the iron exporter protein, ferroportin. Heparin is a highly sulfated glycosaminoglycan released by mast cells and basophils at sites of tissue injury. During Mtb infection, heparin alters intracellular trafficking in alveolar epithelial cells and decreases extrapulmonary dissemination but recently, heparin also has been reported to inhibit hepcidin expression in hepatocytes, decreasing intracellular iron availability. In this report, we demonstrate that heparin significantly reduces hepcidin expression in macrophages infected with Mtb bacilli. Heparin-treated macrophages have higher ferroportin expression compared to untreated macrophages, promoting iron export and decreasing iron availability to intracellular bacilli. Thus, here we describe a novel immunomodulatory effect and potential therapeutic role for heparin against mycobacterial infection in human macrophages.
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肝素酶的过表达降低了肝素的表达，影响铁稳态并改变对炎症的反应。
影响因子：
3.7
作者：
Asperti M;Stuemler T;Poli M;Gryzik M;Lifshitz L;Meyron-Holtz EG;Vlodavsky I;Arosio P
通讯作者：
Arosio P
影响因子：
6.7
作者：
Cornet, Alexander D.;Smit, Ellen G. M.;Groeneveld, A. B. Johan
通讯作者：
Groeneveld, A. B. Johan
DOI：
10.1054/tuld.1999.0216
发表时间：
1999-01-01
期刊：
Tubercle and Lung Disease
影响因子：
--
作者：
Gomes, M. S.;Dom, G.;Appelberg, R.
通讯作者：
Appelberg, R.
DOI：
10.1073/pnas.1109958109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Madigan, Cressida A.;Cheng, Tan-Yun;Moody, D. Branch
通讯作者：
Moody, D. Branch
影响因子：
5.2
作者：
Forrellad MA;Klepp LI;Gioffré A;Sabio y García J;Morbidoni HR;de la Paz Santangelo M;Cataldi AA;Bigi F
通讯作者：
Bigi F