Intestinal Epithelial Cell-Derived Semaphorin 7A Negatively Regulates Development of Colitis via αvβ1 Integrin
Intestinal Epithelial Cell-Derived Semaphorin 7A Negatively Regulates Development of Colitis via αvβ1 Integrin
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DOI：
10.4049/jimmunol.1102084
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
--
作者：
Kang, Sujin;Okuno, Tatsusada;Kumanogoh, Atsushi
肠道免疫系统不断受到肠道细菌的挑战;因此，它必须通过几种调节机制保持静止。虽然肠道巨噬细胞（M phi s）参与抑制过度炎症，但仍不清楚它们的功能在炎症过程中是如何调节的。在这项研究中，我们报告，脑信号蛋白7A（Sema 7A），一个GPI锚定的脑信号蛋白表达在肠上皮细胞（IEC），诱导IL-10的肠M φ s的生产调节肠道炎症。由于肠道IL-10水平降低，Sema 7A缺陷小鼠显示出葡聚糖硫酸钠诱导的结肠炎的严重体征。我们进一步鉴定了CX 3CR 1（+）MHCII类（int）F4/80（hi）CD 11b（hi）M phi s作为IL-10的主要产生者，其通过α v β 1整联蛋白应答Sema 7A。值得注意的是，Sema 7A主要在IEC的基底外侧表达，并且其表达模式负责对葡聚糖硫酸钠诱导的结肠炎的保护作用以及在IEC和M phi之间的相互作用期间M phi s产生的IL-10。此外，我们确定了重组Sema 7A蛋白的施用改善了结肠炎的严重程度，并且这些作用被IL-10阻断Ab减弱。因此，我们的研究结果不仅表明Sema 7A通过α v β 1整联蛋白在抑制肠道炎症中起关键作用，而且还提供了一种通过IEC和M phi之间的相互作用诱导IL-10的新模式。免疫学杂志，2012，188：1108-1116。
The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (M phi s) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI-anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL-10 production by intestinal M phi s to regulate intestinal inflammation. Sema7A-deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1(+)MHC class II(int)F4/80(hi)CD11b(hi) M phi s as the main producers of IL-10 via alpha v beta 1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by M phi s during interactions between IECs and M phi s. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10-blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through alpha v beta 1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and M phi s. The Journal of Immunology, 2012, 188: 1108-1116.