Kataru Raghu P, Park Hyeung Ju, Shin Jinyeon, Baik Jung Eun, Sarker Ananta, Brown Stav, Mehrara Babak J
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Front Aging. 2022 Apr 4;3:864860. doi: 10.3389/fragi.2022.864860. eCollection 2022.
Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.
淋巴结构和功能在液体运输、抗原递呈及免疫稳态中发挥着关键作用。功能失调的淋巴系统与外周组织的慢性低度炎症、免疫反应不佳及反复感染相关，而这些也是衰老病理学的特征。先前的研究表明，衰老会损害包括肠道和中枢神经系统在内的多种器官系统中的淋巴结构和功能。然而，先前的研究大多局限于对淋巴结构变化的定性分析以及对肠道集合淋巴管收缩功能的量化。目前尚不清楚淋巴功能下降是否会导致与衰老相关的病理状况，也不清楚它如何影响皮肤免疫微环境。此外，衰老对皮肤初始淋巴管和集合淋巴管、树突状细胞（DC）迁移、皮肤淋巴泵血以及淋巴管内皮细胞（LEC）中的VEGFR-3信号传导的影响尚未进行定量分析。在此，我们使用荧光免疫组织化学和流式细胞术证实，衰老会降低皮肤初始淋巴管和集合淋巴管的密度。吲哚菁绿（ICG）淋巴管造影和DC迁移试验证实，衰老会降低通过淋巴管的液体泵血和细胞迁移。在细胞水平上，衰老导致VEGFR-3信号传导减少，导致LEC凋亡和衰老增加。最后，我们确定衰老会导致淋巴管趋化因子产生减少，并改变LEC中连接分子和粘附分子的表达。这反过来又导致淋巴管周围炎症和亚硝化应激增加，可能以前馈方式促成衰老病理学。综上所述，我们的研究除了定量证实先前的发现外，还提出了多种导致衰老中淋巴功能障碍的机制，这些机制进而以前馈方式加剧衰老病理学。
