美国伊利诺斯大学医学院Asrar B. Malik和Jalees Rehman研究组取得一项新突破。他们发现血管分泌的Rspondin3通过代谢表观遗传重编程指导间质巨噬细胞的转变，并减轻炎性损伤。这一研究成果于2020年8月24日发表在《自然-免疫学》杂志上。

他们发现，针对炎症损伤，肺内皮细胞释放出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的辅助因子，来催化DNA羟甲基化。

值得注意的是，Rspondin3的内皮特异性缺失，阻止了内毒素血症小鼠中抗炎性间质巨噬细胞的形成，并引起了不受控制的严重炎性损伤。因此，内皮细胞指定的血管分泌－代谢－表观遗传信号转导，对于重编程间质巨噬细胞和减轻炎症损伤至关重要。

据悉，巨噬细胞显示出显著的可塑性，这对于宿主防御和组织修复至关重要。组织微环境印记巨噬细胞身份、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。此外，肺是高度血管化的器官，并充满大量常驻巨噬细胞。

附：英文原文

Title: The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic–epigenetic reprogramming and resolves inflammatory injury

Author: Bisheng Zhou, Lissette Magana, Zhigang Hong, Long Shuang Huang, Sreeparna Chakraborty, Yoshikazu Tsukasaki, Cary Huang, Li Wang, Anke Di, Balaji Ganesh, Xiaopei Gao, Jalees Rehman, Asrar B. Malik

Issue&Volume: 2020-08-24

Abstract: 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.

DOI: 10.1038/s41590-020-0764-8

Source: https://www.nature.com/articles/s41590-020-0764-8