Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress

Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, alpha 9 integrin, which is closely associated with activated beta 1 integrin, and its ligand, tenascin-C, colocalize on medullary and cortical sinuses of draining lymph nodes (dLNs), which is a gate for lymphocyte exit, and that inhibition of lymphocyte egress is evident by blockade of alpha 9 integrin-mediated signaling at dLNs. Based on in vitro analysis using lymphatic endothelial cells obtained from mice embryos, we suggested the possibility that stimulation of lymphatic endothelial cells by tenascin-C enhances S1P secretion in an alpha 9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of alpha 9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating alpha 9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders.

1 -磷酸鞘氨醇（S1P）在淋巴细胞从淋巴器官迁出过程中发挥作用。然而，S1P的产生和分泌是如何被调控的仍不清楚。我们发现，在炎症条件下，与活化的β1整合素密切相关的α9整合素及其配体腱生蛋白-C共定位在引流淋巴结（dLNs）的髓窦和皮质窦上，这里是淋巴细胞迁出的通道，并且通过阻断dLNs处α9整合素介导的信号传导，淋巴细胞迁出明显受到抑制。基于对从小鼠胚胎获取的淋巴管内皮细胞的体外分析，我们提出一种可能性，即腱生蛋白 - C对淋巴管内皮细胞的刺激以α9整合素依赖的方式增强S1P的分泌，而不影响S1P的合成和/或降解。在包括实验性自身免疫性脑脊髓炎在内的几种模型中，阻断α9整合素介导的信号传导减少了淋巴细胞从dLNs迁出，并且在实验性自身免疫性脑脊髓炎中改善了临床评分和病理状况。因此，调控α9整合素的功能可能为治疗各种炎症性疾病提供一种治疗策略。