In response to signals associated with infection or tissue damage, macrophages undergo a series of dynamic phenotypic changes. Here we show that during the response to lipopolysaccharide and interferon-γ stimulation, metabolic reprogramming in macrophages is also highly dynamic. Specifically, the tricarboxylic acid cycle undergoes a two-stage remodelling: the early stage is characterized by a transient accumulation of intermediates including succinate and itaconate, whereas the late stage is marked by the subsidence of these metabolites. The metabolic transition into the late stage is largely driven by the inhibition of the pyruvate dehydrogenase complex (PDHC) and the oxoglutarate dehydrogenase complex (OGDC), which is controlled by the dynamic changes in the lipoylation state of both PDHC and OGDC E2 subunits and phosphorylation of the PDHC E1 subunit. This dynamic metabolic reprogramming results in a transient metabolic state that strongly favours hypoxia-inducible factor-1α (HIF-1α) stabilization during the early stage, which subsides by the late stage; consistently, HIF-1α levels follow this trend. This study elucidates a dynamic and mechanistic picture of metabolic reprogramming in lipopolysaccharide and interferon-γ stimulated macrophages, and provides insights into how changing metabolism can regulate the functional transitions in macrophages over the course of an immune response.

为了响应与感染或组织损伤相关的信号，巨噬细胞经历一系列动态表型变化。在这里，我们表明，在对脂多糖和干扰素-γ刺激的反应过程中，巨噬细胞的代谢重编程也是高度动态的。具体来说，三羧酸循环经历了两阶段重塑：早期阶段的特点是琥珀酸和衣康酸等中间体的短暂积累，而晚期阶段的特点是这些代谢物的沉降。进入晚期的代谢转变很大程度上是由丙酮酸脱氢酶复合物（PDHC）和氧化戊二酸脱氢酶复合物（OGDC）的抑制驱动的，这是由PDHC和OGDC E2亚基的脂酰化状态和磷酸化的动态变化控制的PDHC E1 亚基。这种动态代谢重编程会导致短暂的代谢状态，该状态在早期阶段强烈有利于缺氧诱导因子-1α（HIF-1α）的稳定，并在晚期阶段消退； HIF-1α 水平始终遵循这一趋势。这项研究阐明了脂多糖和干扰素-γ刺激的巨噬细胞中代谢重编程的动态和机制图，并提供了关于改变代谢如何在免疫反应过程中调节巨噬细胞功能转变的见解。