A Blunted GPR183/Oxysterol Axis During Dysglycemia Results in Delayed Recruitment of Macrophages to the Lung During Mycobacterium tuberculosis Infection

Minh Dao Ngo, Stacey Bartlett, H. Bielefeldt-Ohmann, Cheng Xiang Foo, Roma Sinha, Buddhika Jayakody Arachige, Sarah Reed, T. Mandrup-Poulsen, M. Rosenkilde, K. Ronacher
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引用次数: 3

Abstract

Abstract Background We previously reported that reduced GPR183 expression in blood from tuberculosis (TB) patients with diabetes is associated with more severe TB. Methods To further elucidate the role of GPR183 and its oxysterol ligands in the lung, we studied dysglycemic mice infected with Mycobacterium tuberculosis (Mtb). Results We found upregulation of the oxysterol-producing enzymes CH25H and CYP7B1 and increased concentrations of 25-hydroxycholesterol upon Mtb infection in the lungs of mice. This was associated with increased expression of GPR183 indicative of oxysterol-mediated recruitment of GPR183-expressing immune cells to the lung. CYP7B1 was predominantly expressed by macrophages in TB granulomas. CYP7B1 expression was significantly blunted in lungs from dysglycemic animals, which coincided with delayed macrophage infiltration. GPR183-deficient mice similarly had reduced macrophage recruitment during early infection. Conclusions Taken together, we demonstrate a requirement of the GPR183/oxysterol axis for positioning of macrophages to the site of infection and add an explanation to more severe TB in diabetes patients.
血糖异常时GPR183/羟甾醇轴钝化导致结核分枝杆菌感染期间巨噬细胞向肺的延迟募集
我们之前报道过,糖尿病结核病患者血液中GPR183表达降低与更严重的结核病有关。方法以感染结核分枝杆菌(Mtb)的血糖异常小鼠为研究对象,进一步阐明GPR183及其氧甾醇配体在肺中的作用。结果我们发现结核分枝杆菌感染小鼠肺中产生氧甾醇的酶CH25H和CYP7B1上调,25-羟基胆固醇浓度升高。这与GPR183表达增加有关,表明氧甾醇介导的表达GPR183的免疫细胞向肺募集。CYP7B1在结核肉芽肿中主要由巨噬细胞表达。在血糖异常动物的肺中,CYP7B1的表达明显减弱,这与巨噬细胞浸润延迟一致。gpr183缺陷小鼠在早期感染时同样减少巨噬细胞募集。综上所述,我们证明了巨噬细胞定位到感染部位需要GPR183/羟甾醇轴,并为糖尿病患者中更严重的结核病提供了解释。
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