Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular–cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.

解决型巨噬细胞通过胞吞作用清除凋亡细胞，从而预防慢性炎症。这些巨噬细胞被认为主要依赖于氧化磷酸化，但新出现的证据表明胞吞作用和糖酵解之间可能存在联系。为了进一步了解这个问题，我们研究了胞吞作用诱导的巨噬细胞糖酵解及其后果所涉及的分子细胞机制。我们发现胞吞作用促进巨噬细胞糖酵解的短暂增加，这依赖于 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 2 (PFKFB2) 酶的快速激活，这将这一过程与促炎中的糖酵解区分开来。巨噬细胞。与野生型对照小鼠相比，移植有活化缺陷的PFKFB2骨髓，然后进行地塞米松诱导的胸腺细胞凋亡的小鼠表现出胸腺胞吞作用受损、胸腺坏死增加以及胸腺巨噬细胞上胞吞作用受体MerTK和LRP1的表达降低。体外机制研究表明，第一个凋亡细胞的摄取刺激糖酵解，通过乳酸介导的 MerTK 和 LRP1 上调促进持续的胞吞作用。因此，胞吞作用诱导的巨噬细胞糖酵解代表了一种独特的代谢过程，它以乳酸依赖性方式维持持续​​的胞吞作用。这一过程与炎症巨噬细胞糖酵解的区别提出了一种可能性，即可以在治疗上增强它以促进慢性炎症疾病的胞吞作用和消退。