Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.
Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.
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淋巴 S1P 信号异常会加剧淋巴功能障碍和组织炎症。
DOI：
10.1101/2023.06.08.23291175
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Jiang,Xin
中科院分区：
文献类型：
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作者：
Kim,Dongeon;Tian,Wen;Wu,TimothyTing-Hsuan;Xiang,Menglan;Vinh,Ryan;Chang,Jason;Gu,Shenbiao;Lee,Seunghee;Zhu,Yu;Guan,Torrey;Schneider,EmilieClaire;Bao,Evan;Dixon,JBrandon;Kao,Peter;Pan,Junliang;Rockson,StanleyG;Jiang,Xin
背景：淋巴水肿是一个全球性的健康问题，没有有效的药物治疗。增强的t细胞免疫和异常的淋巴内皮细胞（LEC）信号是治疗这种疾病的有希望的靶点。鞘氨醇-1-磷酸（S1P）介导了LEC正常功能所需的关键信号通路，LEC中S1P信号的改变可导致淋巴疾病和致病性t细胞活化。描述这种生物学特性与开发急需的治疗方法有关。方法对人和小鼠淋巴水肿进行研究。通过手术结扎小鼠尾部淋巴诱导淋巴水肿。评估淋巴水肿真皮组织的S1P信号。为了验证改变的S1P信号在淋巴细胞中的作用，我们产生了lec特异性s1pr1缺陷（S1pr1LECKO）小鼠。随着时间的推移，通过尾体积和组织病理学测量来量化疾病进展。然后，将S1P信号抑制的小鼠和人lec与CD4 T细胞共培养，然后分析CD4 T细胞的活化和途径信号。最后，用p -选择素特异性单克隆抗体治疗动物，以评估其减少淋巴水肿和t细胞活化的功效。结果人和实验淋巴水肿组织通过S1P受体1 （S1PR1）表达LEC S1P信号减少。在小鼠淋巴水肿中，lecs1pr1功能丧失加重了淋巴血管功能不全、尾部肿胀和CD4 t细胞浸润增加。从ms1pr1leckomice中分离出LECs并与CD4 T细胞共培养，可增强淋巴细胞分化。抑制人真皮LECs中的S1PR1信号，通过与淋巴细胞直接接触促进t辅助型1和2 （Th1和Th2）细胞的分化。S1P信号被抑制的人真皮LECs表现出p -选择素的增强，p -选择素是一种重要的细胞粘附分子，在活化的血管细胞上表达。在体外，p -选择素阻断降低了Th细胞与shs1pr1处理的人真皮LECs共培养的活化和分化。p选择素定向抗体治疗可改善小鼠淋巴水肿的尾部肿胀并降低Th1/Th2免疫反应。结论LEC S1P信号的减少通过增强LEC粘附和增强致病性CD4 t细胞反应而加重淋巴水肿。p -选择素抑制剂被认为是这种普遍疾病的可能治疗方法。
BACKGROUNDLymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies.METHODSHuman and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specificS1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation.RESULTSHuman and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LECS1pr1loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated fromS1pr1LECKOmice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured withshS1PR1-treated human dermal LECs. P-selectin–directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema.CONCLUSIONSThis study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.