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Immunity 湖南师大翟宗昭组发现天然免疫通路在肠道上皮脱落中的关键作用

2018-05-16 BioArt BioArt

动物肠道上皮不仅是消化吸收的场所,也作为机体的第一道防线发挥着重要的屏障功能。持续的干细胞分裂分化以及肠上皮细胞脱落构筑了高度动态性的肠道上皮。据估计,人体小肠每天脱落上皮细胞可达数百亿个。异常的上皮细胞脱落破坏肠道屏障完整性,是肠道炎症发生的根本原因。然而,激活肠上皮细胞脱落的信号途径目前还不清楚。

动物肠道上皮不仅是消化吸收的场所,也作为机体的第一道防线发挥着重要的屏障功能。持续的干细胞分裂分化以及肠上皮细胞脱落构筑了高度动态性的肠道上皮。据估计,人体小肠每天脱落上皮细胞可达数百亿个。异常的上皮细胞脱落破坏肠道屏障完整性,是肠道炎症发生的根本原因。然而,激活肠上皮细胞脱落的信号途径目前还不清楚。

5月8日,湖南师范大学生命科学学院翟宗昭课题组与瑞士洛桑联邦理工大学Bruno Lemaitre教授合作在Immunity杂志在线发表了题为“Cell-specific Imd-NF-κB responses enable simultaneous antibacterial immunity and intestinal epithelial cell shedding upon bacterial infection”的研究论文,揭示果蝇Imd/NF-κB天然免疫信号通路(与哺乳动物TNFR通路在组成上高度相似)不仅控制抗菌肽的产生以清除侵染细菌,同时也是细菌感染导致的肠上皮细胞脱落所必须的。该发现为全面认识天然免疫通路的细胞功能以及调控肠道上皮细胞脱落和更新的分子机制提供了新见解。据悉,该论文被选为5月15日正式出版的Immunity杂志的封面论文。

果蝇作为重要的遗传学模式生物,已为发育和天然免疫机理方面的研究做出了突出贡献。Bruno Lemaitre教授作为第一作者于1996年前后发表在Cell、PNAS上的三篇论文利用果蝇系统通过遗传方法率先揭示了一个当时命名为Imd(哺乳动物RIP1)的未知突变所定义的信号通路以及Toll受体信号通路 (哺乳动物Toll-like receptor) 在天然免疫识别中的关键作用。这些工作基本搭建了当代无脊椎动物天然免疫研究的框架,利用遗传手段研究天然免疫的成功也开启了随后天然免疫研究爆炸式的发展,推动了哺乳动物相关研究,为其当时合作导师Jules Hoffman获得2011年诺贝尔生理或医学奖铺平了道路。(然而师徒关系不好,2011年诺奖宣布后Bruno Lemaitre通过网站http://www.behinddiscoveries.com/表达了对Jules Hoffman的不快,并试图还原给读者科学发现当时的真相,有兴趣可以初步了解一下。BioArt在适当的时候将会推出详细的专题文章讨论此事。)

与哺乳动物肠道上皮构造方面的相似性也使得果蝇成为研究肠道上皮更新的理想模式。之前结果已经建立起了“肠道上皮细胞-干细胞”的反馈调节机制,即损伤的上皮细胞通过分泌生长因子等来促进干细胞的分裂,进而修补上皮损伤以维持肠道屏障完整性。果蝇JAK/STAT通路的配体Upd2和Upd3属于这一类分子。

在最新的这项研究中,研究人员推测,激活生长因子在受损细胞中表达的转录调控机制很可能同时也是导致上皮细胞脱落的原因。带着这个假设,通过构建报告基因转基因品系,作者首先解析了upd2基因的顺式调控元件并鉴定出一个约200bp的可被细菌感染激活增强子序列。序列分析发现了NF-κB和AP1位点;进一步研究确证了免疫通路Imd/NF-κB和应激通路JNK在调控该增强子激活以及肠上皮细胞脱落中的关键作用。

有意思的是,抗菌肽的表达和上皮细胞脱落两个受Imd信号通路调控的宿主防御机制,发生不同区域的上皮细胞从而保证两个过程可以同时发生。另外,该研究发现,caspase激活导致细胞凋亡并不是上皮细胞脱落发生所必须的,说明细胞脱落的发生是独立于细胞凋亡的过程。该研究建立了一个在脱落肠上皮细胞特异表达的荧光报告基因,在揭示上皮免疫在细胞脱落和更新过程发挥作用的同时,也为深入研究上皮细胞脱落的分子细胞机制提供了有力的工具。



总的来说,该研究的一大亮点是在概念上的创新:通过证明免疫通路在上皮细胞脱落中的作用将上皮细胞的两个关键生物过程联系起来。哺乳动物的研究结果也揭示TNFR和NOD-like受体免疫通路在细菌感染导致的肠上皮细胞脱落中关键作用。于是,这些结果便一同暗示:免疫通路在上皮细胞更新中的作用可能在进化上是保守的。论文审稿人也一致认为这一观念上的创新“fundamentally important”。

翟宗昭博士为论文第一作者和第一通讯作者。Bruno Lemaitre教授为文章的senior author。

原始出处:
Zhai Z, Boquete JP, Lemaitre B.Cell-Specific Imd-NF-κB Responses Enable Simultaneous Antibacterial Immunity and Intestinal Epithelial Cell Shedding upon Bacterial Infection.Immunity. 2018 May 3. pii: S1074-7613(18)30179-1. doi: 10.1016/j.immuni.2018.04.010. [Epub ahead of print]

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    2018-05-27 1e0f8808m18(暂无匿称)

    学习了.谢谢分享!

    0

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    2018-05-16 120b86f8m56暂无昵称

    厉害

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=2043528, encodeId=5ded2043528ca, content=<a href='/topic/show?id=eab344152ba' target=_blank style='color:#2F92EE;'>#天然免疫通路#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=116, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=44152, encryptionId=eab344152ba, topicName=天然免疫通路)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=11b4465, createdName=ying_wu, createdTime=Sat Dec 22 03:48:00 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1797064, encodeId=621f1e9706494, content=<a href='/topic/show?id=045222331db' target=_blank style='color:#2F92EE;'>#中的关键作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=98, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22331, encryptionId=045222331db, topicName=中的关键作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=373a131, createdName=jxrzshh, createdTime=Tue Jun 19 16:48:00 CST 2018, time=2018-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2030376, encodeId=f22720303e68a, content=<a href='/topic/show?id=25079e7287' target=_blank style='color:#2F92EE;'>#Immunity#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9772, encryptionId=25079e7287, topicName=Immunity)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/C4Qhy5XHSe503Qbjzc1UtDR83BCv66o6P2XRedX9ohsNGa3uEVicFFk2qkuX5zBSmpicepFySBrwoYknhqMdKmtw/132, createdBy=1aca2500179, createdName=12498d2fm51(暂无昵称), createdTime=Mon Dec 17 17:48:00 CST 2018, time=2018-12-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=318862, encodeId=eb743188629c, content=学习了.谢谢分享!, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=60791943465, createdName=1e0f8808m18(暂无匿称), createdTime=Sun May 27 00:14:50 CST 2018, time=2018-05-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1481287, encodeId=8433148128e56, content=<a href='/topic/show?id=c5534414ee6' target=_blank style='color:#2F92EE;'>#天然免疫#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=44147, encryptionId=c5534414ee6, topicName=天然免疫)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Fri May 18 05:48:00 CST 2018, time=2018-05-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=315707, encodeId=1bc4315e0720, content=厉害, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2017/12/08/0f56ebd204ba7622791c5f4c5ae744ff.jpg, createdBy=7b1d2201969, createdName=120b86f8m56暂无昵称, createdTime=Wed May 16 18:11:22 CST 2018, time=2018-05-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=315669, encodeId=5f433156695d, content=很好.前进的步伐, beContent=null, objectType=article, channel=null, level=null, likeNumber=134, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKibA62IFMeUJEmSyIe8DvYFeERuOsfrRd8iano7nENqQU1dRR3tqeQOUL3eqgYgEZRT2t2iaEsib0JEw/132, createdBy=66771693911, createdName=易水河, createdTime=Wed May 16 15:31:18 CST 2018, time=2018-05-16, status=1, ipAttribution=)]
    2018-05-16 易水河

    很好.前进的步伐

    0

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