Table_2_Lymph Leakage Promotes Immunosuppression by Enhancing Anti-Inflammatory Macrophage Polarization.xlsx

Lymphatic vasculature is a network of capillaries and vessels capable of draining extracellular fluid back to blood circulation and to facilitate immune cell migration. Although the role of the lymphatic vasculature as coordinator of fluid homeostasis has been extensively studied, the consequences of abnormal lymphatic vasculature function and impaired lymph drainage have been mostly unexplored. Here, by using the Prox1+/– mice with defective lymphatic vasculature and lymphatic leakage, we provide evidence showing that lymph leakage induces an immunosuppressive environment by promoting anti-inflammatory M2 macrophage polarization in different inflammatory conditions. In fact, by using a mouse model of tail lymphedema where lymphatic vessels are thermal ablated leading to lymph accumulation, an increasing number of anti-inflammatory M2 macrophages are found in the lymphedematous tissue. Moreover, RNA-seq analysis from different human tumors shows that reduced lymphatic signature, a hallmark of lymphatic dysfunction, is associated with increased M2 and reduced M1 macrophage signatures, impacting the survival of the patients. In summary, we show that lymphatic vascular leakage promotes an immunosuppressive environment by enhancing anti-inflammatory macrophage differentiation, with relevance in clinical conditions such as inflammatory bowel diseases or cancer.

淋巴管系统（Lymphatic vasculature）是由毛细血管与淋巴管组成的网络，可将细胞外液回流至血液循环，并促进免疫细胞迁移。尽管学界已对淋巴管系统调控体液稳态的功能开展了广泛研究，但淋巴管功能异常与淋巴引流受损所导致的后果，迄今仍未得到充分探索。本研究借助淋巴管功能缺陷且存在淋巴渗漏（lymphatic leakage）的Prox1+/–小鼠模型，证实淋巴渗漏可在多种炎症状态下通过促进抗炎型M2巨噬细胞极化（anti-inflammatory M2 macrophage polarization），诱导免疫抑制微环境（immunosuppressive environment）的形成。具体而言，在尾部淋巴水肿（tail lymphedema）小鼠模型中，淋巴管经热消融（thermally ablated）后会引发淋巴液蓄积，研究人员在水肿组织中观测到抗炎型M2巨噬细胞的数量逐渐增多。此外，对不同人类肿瘤的RNA测序（RNA-seq）分析结果显示，淋巴功能障碍的标志性特征——淋巴特征基因谱（lymphatic signature）表达下调——与M2巨噬细胞特征基因谱表达上调、M1巨噬细胞特征基因谱表达下调相关，并会对患者的生存预后产生影响。综上，本研究证实淋巴管渗漏可通过增强抗炎型巨噬细胞分化，诱导免疫抑制微环境，该机制在炎症性肠病（inflammatory bowel diseases）、癌症等临床疾病中具有重要意义。