Macrophages demonstrate remarkable plasticity that is essential for host defense and tissue repair. The tissue niche imprints macrophage identity, phenotype and function. The role of vascular endothelial signals in tailoring the phenotype and function of tissue macrophages remains unknown. The lung is a highly vascularized organ and replete with a large population of resident macrophages. We found that, in response to inflammatory injury, lung endothelial cells release the Wnt signaling modulator Rspondin3, which activates β-catenin signaling in lung interstitial macrophages and increases mitochondrial respiration by glutaminolysis. The generated tricarboxylic acid cycle intermediate α-ketoglutarate, in turn, serves as the cofactor for the epigenetic regulator TET2 to catalyze DNA hydroxymethylation. Notably, endothelial-specific deletion of Rspondin3 prevented the formation of anti-inflammatory interstitial macrophages in endotoxemic mice and induced unchecked severe inflammatory injury. Thus, the angiocrine–metabolic–epigenetic signaling axis specified by the endothelium is essential for reprogramming interstitial macrophages and dampening inflammatory injury.

巨噬细胞显示出显着的可塑性，这对于宿主防御和组织修复至关重要。组织利基印记巨噬细胞身份，表型和功能。血管内皮信号在调整组织巨噬细胞表型和功能中的作用仍然未知。肺是高度血管化的器官，并充满大量常驻巨噬细胞。我们发现，针对炎症损伤，肺内皮细胞释放Wnt信号调节剂Rspondin3，后者激活肺间质巨噬细胞中的β-catenin信号并通过谷氨酰胺分解增加线粒体呼吸。生成的三羧酸循环中间体α-酮戊二酸又充当表观遗传调节剂TET2催化DNA羟甲基化的辅助因子。值得注意的是 Rspondin3的内皮特异性删除阻止了内毒素血症小鼠中抗炎性间质巨噬细胞的形成，并引起了未经检查的严重炎性损伤。因此，由内皮指定的血管分泌－代谢－表观遗传信号轴对于重编程间质巨噬细胞和减轻炎症损伤至关重要。