Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

This is the dataset pertaining to the article "Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses". To interpret and follow the data, please refer to the linked article, as each excel sheet corresponds with each named graph/figure. Abstract: Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the “classically activated” M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, “alternatively activated” M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

本数据集关联论文《IL-4与IL-13激活诱导的巨噬细胞先天训练增强氧化磷酸化（oxidative phosphorylation，缩写OXPHOS）驱动的抗分枝杆菌应答》。若需解读本数据集，请参阅关联论文，其中每个Excel工作表均对应一篇命名图形或图版。

摘要：巨噬细胞是一类具有高度适应性的先天免疫细胞群。经干扰素γ（Interferon-γ，缩写IFNγ）与脂多糖（Lipopolysaccharide，缩写LPS）极化为“经典活化型”M1巨噬细胞后，可增强促炎与杀菌应答，这对清除结核分枝杆菌（Mycobacterium tuberculosis）等致病菌至关重要。与之相反，经IL-4极化为“交替活化型”M2巨噬细胞则会抑制杀菌机制，促进分枝杆菌增殖。上述两种活化状态伴随截然不同的代谢特征：M1巨噬细胞几乎完全依赖糖酵解（glycolysis）供能，而M2巨噬细胞则会上调OXPHOS。本研究证实，经IL-4与IL-13活化后，会反直觉地诱导出针对分枝杆菌攻击的保护性先天记忆。在人类与小鼠模型中，预先经IL-4/13活化的巨噬细胞，在受到分枝杆菌配体的二次刺激时，其促炎细胞因子的分泌量会显著提升。在本研究的小鼠模型中，同样观察到杀菌能力的增强。尽管表型发生了这种转变，经IL-4/13训练的小鼠巨噬细胞并未呈现M1型典型代谢特征，反而仍维持较高水平的OXPHOS活性。此外，使用寡霉素（oligomycin）、2-脱氧葡萄糖（2-deoxyglucose）或BPTES抑制OXPHOS，均会削弱经IL-4/13训练的巨噬细胞所产生的增强型促炎细胞因子应答。最后，本研究发现IL-10会减弱IL-4/13诱导的保护性训练效应，抑制促炎与杀菌机制。综上，本研究为分枝杆菌感染背景下的巨噬细胞交替活化状态提供了全新且反直觉的研究视角。