Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.
Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.
复制标题
接触烟草烟雾会招募炎症性空腔单核细胞，为结核分枝杆菌建立允许的肺部生态位。
DOI：
10.1126/scitranslmed.adg3451
复制
发表时间：
2023
影响因子：
17.1
通讯作者：
Kwon,DouglasS
中科院分区：
文献类型：
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作者：
Corleis,Björn;Tzouanas,ConstantineN;Wadsworth2nd,MarcH;Cho,JosalynL;Linder,AliceH;Schiff,AbigailE;Zessin,Björn;Stei,Fabian;Dorhoi,Anca;Dickey,AmyK;Medoff,BenjaminD;Shalek,AlexK;Kwon,DouglasS
吸烟使活动性结核病（TB）的风险增加一倍，占全球所有活动性结核病病例的20%。吸烟如何促进肺微环境允许结核分枝杆菌（Mtb）的生长仍不完全清楚。我们通过进行单细胞RNA测序（scRNA-seq）、流式细胞术和功能测定，研究了当前和从不吸烟者的原代支气管肺泡灌洗液细胞。我们观察到与非吸烟者相比，吸烟者肺中未成熟炎性单核细胞的富集。这些单核细胞表现出的表型与近期从血液中募集、持续分化、活化增加以及与慢性阻塞性肺疾病相似的状态一致。使用整合scRNA-seq和流式细胞术，我们鉴定了CD 93作为这些新募集的吸烟相关肺单核细胞的亚群的标志物，并进一步提供了证据表明单核细胞向肺中的募集是由CCR 2结合趋化因子（包括CCL 11）介导的。我们还发现，这些细胞暴露于结核分枝杆菌后炎症反应增强，与成熟的巨噬细胞相比，结核分枝杆菌细胞内生长加速。这种升高的结核分枝杆菌生长可以被抗炎小分子抑制，这提供了吸烟诱导的促炎状态和结核分枝杆菌生长的许可之间的联系。我们的研究结果表明，吸烟导致未成熟的炎症单核细胞从外周招募到肺，这导致这些Mtb-容许细胞在气道中的积累。这项工作定义了吸烟如何导致对结核病的易感性增加，并确定了针对宿主的治疗方法，以减少吸烟者的结核病负担。
Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive toMycobacterium tuberculosis(Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure toMtband accelerated intracellular growth ofMtbcompared with mature macrophages. This elevatedMtbgrowth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness toMtbgrowth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of theseMtb-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility toMtband identifies host-directed therapies to reduce the burden of TB among those who smoke.