Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm.
Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm.
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DOI：
10.1084/jem.20101138
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发表时间：
2010-12-20
期刊：
影响因子：
--
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
Wen H;Lei Y;Eun SY;Ting JP
丛蛋白a4活性对于toll样受体诱导的信号传导、细胞因子产生和小鼠炎症至关重要。丛蛋白和信号蛋白是神经系统中作为引导分子的配体-受体对，在免疫中起一定作用。丛蛋白与toll样受体（TLRs）在从果蝇到哺乳动物的进化保护过程中相似。通过研究丛蛋白- a4缺陷（Plxna4−/−）先天免疫细胞，我们发现了丛蛋白- a4对TLR信号传导的新影响。Plxna4 - / -细胞在TLR激动剂和细菌的激活下表现出炎症细胞因子产生缺陷。tlr诱导的小鸟苷三磷酸水解酶（GTPase） Rac1 （ras相关C3肉毒毒素底物1）的激活需要Plexin-A4。Rac1的激活伴随着JNK （c-Jun n -末端激酶）和NF-κB的激活，最终导致tlr诱导NF-κB和AP-1与炎症细胞因子的启动子结合。Plxna4 - / -小鼠对TLR激动剂引起的炎症和盲肠结扎穿刺引起的多微生物腹膜炎具有明显的抗性。丛蛋白a4配体Sema3A（信号蛋白3A）的使用会加剧TLR激动剂和细菌性脓毒症引起的细胞因子风暴。TLR参与可以诱导Sema3A表达，从而完成一个自分泌循环。这些发现扩大了丛蛋白对TLR信号的作用，提示丛蛋白a4和Sema3A可作为治疗脓毒症的新干预点。
Plexin-A4 activity is essential for Toll-like receptor–induced signaling, cytokine production, and inflammation in mice. Plexins and semaphorins are ligand–receptor pairs that serve as guidance molecules in the nervous system and play some roles in immunity. Plexins are similar to the Toll-like receptors (TLRs) in their evolutionary conservation from flies to mammals. By studying plexin-A4–deficient (Plxna4−/−) innate immune cells, in this study we show a novel influence of plexin-A4 on TLR signaling. Plxna4−/− cells exhibit defective inflammatory cytokine production upon activation by a spectrum of TLR agonists and bacteria. Plexin-A4 is required for TLR-induced activation of the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). Rac1 activation is accompanied by JNK (c-Jun N-terminal kinase) and NF-κB activation, culminating in TLR-induced binding of NF-κB and AP-1 to the promoters of inflammatory cytokines. Plxna4−/− mice are remarkably resistant to TLR agonist–induced inflammation and polymicrobial peritonitis caused by cecal ligation and puncture. Administration of a ligand of plexin-A4, Sema3A (semaphorin 3A), exacerbates the cytokine storm caused by TLR agonists and bacterial sepsis. TLR engagement can induce Sema3A expression, thus completing an autocrine loop. These findings expand the role of plexins to TLR signaling and suggest plexin-A4 and Sema3A as new intervention points for treating sepsis.
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