Integrin-Alpha IIb Identifies Murine Lymph Node Lymphatic Endothelial Cells Responsive to RANKL.
Integrin-Alpha IIb Identifies Murine Lymph Node Lymphatic Endothelial Cells Responsive to RANKL.
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DOI：
10.1371/journal.pone.0151848
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Mueller CG
中科院分区：
文献类型：
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作者：
Cordeiro OG;Chypre M;Brouard N;Rauber S;Alloush F;Romera-Hernandez M;Bénézech C;Li Z;Eckly A;Coles MC;Rot A;Yagita H;Léon C;Ludewig B;Cupedo T;Lanza F;Mueller CG
微环境和激活信号可能在淋巴管内皮细胞（LEC）群体中留下异质性的印记。特别是次级淋巴器官的LEC暴露于不同的细胞类型和免疫刺激。然而，我们对LEC激活信号的性质及其在稳态下次级淋巴器官内的细胞来源的理解仍然不完整。在这里，我们表明，整合素α 2b（ITGA 2b），已知由血小板，巨核细胞和造血祖细胞进行，是由淋巴结亚群的LEC，居住在髓质，皮质和包膜下窦表达。在被膜下窦中，底层而不是顶层表达整合素，其被排除在ACKR 4 + LEC之外，但与MAdCAM-1表达重叠。ITGA 2b的表达增加免疫反应，提高了异质性ITGA 2b水平反映暴露于激活信号的变化的可能性。我们发现，NF-κB配体受体激活因子（RANKL）水平的改变，通过过度表达，中和或删除基质边缘网状细胞，影响ITGA 2 B + LEC的比例。淋巴结LEC而非外周LEC表达RANK。此外，我们还发现，光敏素-β受体信号同样调节ITGA 2b + LEC的比例。这些发现表明，基质网状细胞通过RANKL激活LEC，并支持造血细胞源性光毒素的作用。
Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4+ LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b+ LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-β receptor signaling likewise regulated the proportion of ITGA2b+ LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin.