Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States.
Department of Medicine, New Jersey Medical School, Public Health Research Institute, Newark, NJ, United States.
Front Immunol. 2022 May 12;13:859116. doi: 10.3389/fimmu.2022.859116. eCollection 2022.
GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as and . Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against infection.
GM-CSF 是一种重要的细胞因子，可调节单核细胞/巨噬细胞的增殖及其在健康和疾病中的各种功能。尽管越来越多的证据支持 GM-CSF 在抗结核（TB）感染中的免疫中可能发挥主要作用的观点，但 GM-CSF 介导的抗 TB 保护作用的机制在很大程度上仍然未知。在这项研究中，我们检查了来自不同供体的人巨噬细胞分泌的 GM-CSF 水平，以及对感染控制至关重要的 GM-CSF 依赖性细胞过程。虽然不同供体的巨噬细胞产生 GM-CSF 的能力不同，但 GM-CSF 的分泌水平与巨噬细胞的存活以及巨噬细胞内控制 菌之间存在显著相关性。巨噬细胞分泌的 GM-CSF 水平与巨噬细胞内的 负担呈负相关，感染宿主巨噬细胞的存活与其 GM-CSF 水平呈正相关。GM-CSF 依赖性人巨噬细胞的延长存活也与细菌负担的显著降低以及与自我更新/细胞存活相关的基因如 和 的表达增加相关。GM-CSF 在巨噬细胞中的抗体耗竭导致细胞凋亡/坏死性细胞死亡的水平显著升高，同时自噬通量降低。此外，产生更多 GM-CSF 的保护性巨噬细胞会诱导更强的肉芽肿反应，并产生显著增加的 IL-1β、IL-12 和 IL-10 水平，以及降低的 TNF-α和 IL-6 水平。平行地，从活动性 TB 患者的外周血中分离的巨噬细胞显示出控制 细胞内生长的能力降低，并产生显著降低水平的 GM-CSF。值得注意的是，与健康对照相比，活动性 TB 患者的巨噬细胞表现出明显改变的代谢状态，与 GM-CSF 的分泌水平相关。总而言之，这些结果表明，人巨噬细胞产生的 GM-CSF 的相对水平在防止细胞死亡和维持宿主细胞对 感染的保护性分化和代谢状态方面起着关键作用。
