Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation¹. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites², improving insulin sensitivity³ or promoting an immune-tolerant microenvironment that facilitates tumour growth and metastasis⁴. Recently, the metabolic regulation of macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming⁵. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical T helper 2 cell cytokine interleukin-4 to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising reactive oxygen species levels. Reactive oxygen species serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.

巨噬细胞表现出一系列激活状态，从经典激活到替代激活¹。或者，活化的巨噬细胞参与多种病理生理过程，例如限制组织寄生虫²、提高胰岛素敏感性³或促进促进肿瘤生长和转移的免疫耐受微环境⁴。最近，巨噬细胞功能的代谢调节成为焦点，因为经典和替代激活程序都需要特定的调节代谢重编程⁵. 虽然大多数关于免疫代谢的研究都集中在激活以提供能量的分解代谢途径上，但对介导巨噬细胞替代激活的合成代谢途径知之甚少。在这项研究中，我们表明合成代谢转录因子甾醇调节元件结合蛋白 1 (SREBP1) 被激活以响应典型的 T 辅助细胞 2 细胞因子白细胞介素 4，以触发从头脂肪生成 (DNL) 程序，这是一个必要的步骤用于巨噬细胞替代激活。从机制上讲，DNL 消耗 NADPH，将其从细胞抗氧化防御中分离出来并提高活性氧水平。活性氧作为第二信使，发出足够的 DNL 信号，并促进巨噬细胞替代激活。