Laboratorio de Inmunología de Enfermedades Respiratorias, Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167), Toulouse, France.
Front Immunol. 2018 Mar 9;9:459. doi: 10.3389/fimmu.2018.00459. eCollection 2018.
The ability of (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection. We found that TB-PE induced FM differentiation as observed by the increase in lipid bodies, intracellular cholesterol, and expression of the scavenger receptor CD36, as well as the enzyme acyl CoA:cholesterol acyl transferase (ACAT). Importantly, interleukin-10 (IL-10) depletion from TB-PE prevented the augmentation of all these parameters. Moreover, we observed a positive correlation between the levels of IL-10 and the number of lipid-laden CD14 cells among the pleural cells in TB patients, demonstrating that FM differentiation occurs within the pleural environment. Downstream of IL-10 signaling, we noticed that the transcription factor signal transducer and activator of transcription 3 was activated by TB-PE, and its chemical inhibition prevented the accumulation of lipid bodies and ACAT expression in macrophages. In terms of the host immune response, TB-PE-treated macrophages displayed immunosuppressive properties and bore higher bacillary loads. Finally, we confirmed our results using bone marrow-derived macrophage from IL-10 mice demonstrating that IL-10 deficiency partially prevented foamy phenotype induction after Mtb lipids exposure. In conclusion, our results evidence a role of IL-10 in promoting the differentiation of FM in the context of Mtb infection, contributing to our understanding of how alterations of the host metabolic factors may favor pathogen persistence.
（Mtb）在其人体宿主中持续存在依赖于许多免疫逃避策略，例如脂质代谢的失调导致泡沫巨噬细胞（FM）的形成。然而，导致 Mtb 感染的巨噬细胞泡沫表型的特定宿主因素仍然未知。在此，我们旨在确定宿主细胞因子是否有助于 Mtb 感染时 FM 的形成。我们的方法基于使用结核性胸腔积液（TB-PE）的无细胞部分作为在 Mtb 感染期间释放的局部因子的生理来源。我们发现 TB-PE 诱导 FM 分化，如脂滴、细胞内胆固醇和清道夫受体 CD36 以及酶酰基辅酶 A：胆固醇酰基转移酶（ACAT）的表达增加所观察到的。重要的是，从 TB-PE 中耗尽白细胞介素-10（IL-10）可防止所有这些参数的增加。此外，我们观察到在 TB 患者的胸腔细胞中，IL-10 水平与载脂 CD14 细胞的数量之间存在正相关，表明 FM 分化发生在胸腔环境中。在 IL-10 信号下游，我们注意到 TB-PE 激活了转录因子信号转导和转录激活因子 3，其化学抑制可防止巨噬细胞中脂滴的积累和 ACAT 的表达。就宿主免疫反应而言，TB-PE 处理的巨噬细胞表现出免疫抑制特性，并具有更高的细菌负荷。最后，我们使用来自 IL-10 小鼠的骨髓衍生巨噬细胞证实了我们的结果，表明在 Mtb 脂质暴露后，IL-10 缺乏部分阻止了泡沫表型的诱导。总之，我们的结果证明了 IL-10 在促进 Mtb 感染时 FM 的分化中的作用，有助于我们理解宿主代谢因子的改变如何有利于病原体的持续存在。
