Translational Research Institute, Mater Research Institute, The University of Queensland, Brisbane, Australia.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
J Infect Dis. 2022 Jun 15;225(12):2219-2228. doi: 10.1093/infdis/jiac102.
We previously reported that reduced GPR183 expression in blood from tuberculosis (TB) patients with diabetes is associated with more severe TB.
To further elucidate the role of GPR183 and its oxysterol ligands in the lung, we studied dysglycemic mice infected with Mycobacterium tuberculosis (Mtb).
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.
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.
我们之前的报告显示，糖尿病结核病（TB）患者血液中 GPR183 表达减少与更严重的 TB 相关。
为了进一步阐明 GPR183 及其氧化固醇配体在肺部中的作用，我们研究了感染结核分枝杆菌（Mtb）的糖尿病小鼠。
我们发现，在 Mtb 感染小鼠肺部中，氧化固醇产生酶 CH25H 和 CYP7B1 的表达上调，并且 25-羟胆固醇的浓度增加。这与 GPR183 的表达增加有关，表明氧化固醇介导了 GPR183 表达的免疫细胞向肺部的募集。CYP7B1 在 TB 肉芽肿中的巨噬细胞中表达为主。在糖代谢紊乱的动物肺部中，CYP7B1 的表达明显减弱，这与巨噬细胞浸润延迟有关。GPR183 缺陷小鼠在早期感染期间同样存在巨噬细胞募集减少的情况。
综上所述，我们证明了 GPR183/氧化固醇轴对于将巨噬细胞定位到感染部位的必要性，并为糖尿病患者中更严重的 TB 提供了一种解释。
