Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobial defense.
Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobial defense.
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DOI：
10.1371/journal.ppat.1003261
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Chen XM
中科院分区：
文献类型：
--
作者：
Hu G;Gong AY;Roth AL;Huang BQ;Ward HD;Zhu G;Larusso NF;Hanson ND;Chen XM
外切小体是由大多数细胞类型从多囊泡内小体释放的膜性纳米囊泡。据推测，它们将分子转移到邻近或远处的细胞，并调节许多生理和病理过程。从胃肠道上皮释放到基底外侧的外切体与抗原提呈有关。在这里，我们报告了胆管和肠道上皮细胞外体的腔内释放增加后，原虫寄生虫微小隐孢子虫感染。胞外体的释放涉及通过促进SNAP23相关的囊泡胞吐过程来激活TLR4/IKK2信号。通过激活TLR4信号，下调let-7家族miRNAs的表达，增加SNAP23的表达，协调外体释放对微小弧菌感染的反应。有趣的是，外切体携带上皮细胞来源的抗菌肽，包括内毒素-37和β-防御素2。TLR4信号的激活增强了上皮抗菌肽的外体穿梭。微小隐孢子虫子孢子暴露在释放的外体中，在体外和体外都会降低它们的存活率和感染力。抗C-C抗体需要与微小隐孢子虫的子孢子表面直接结合。释放的外切体的细小活性。胆管上皮细胞也可增加胞外体的释放，并显示胞外体相关的抗C抗体。细菌脂多糖刺激后小鼠的活动。我们的数据表明，TLR4信号调节管腔外切体的释放和胃肠上皮抗菌肽的穿梭，揭示了与抗菌防御相关的粘膜免疫的新臂。外体是由多种细胞产生的分泌膜状纳米囊泡。胞外体穿梭各种分子，将它们转移到邻近或远处的细胞，并被认为是细胞间通讯的媒介，调节生理和病理过程。在这里，我们报告外体囊泡的腔释放是Toll样受体4(TLR4)相关的胃肠上皮细胞防御微小隐孢子虫感染的重要组成部分，隐孢子虫是一种专有的细胞内原虫，感染胃肠上皮细胞。微小隐孢子虫感染后宿主上皮细胞TLR4信号的激活促进了上皮外切体的腔内释放和抗菌肽在上皮细胞外的穿梭。通过与微小隐孢子虫表面的直接结合，胞外体小泡显示抗隐孢子虫的能力。小胎盘活动。脂多糖刺激后上皮细胞中TLR4信号的激活也增加了胞外体的释放和胞外体相关的抗C抗体。小胎盘活动。因此，我们推测TLR4介导的外切体释放可能与黏膜天然免疫有关，为黏膜表面感染性疾病的治疗干预提供了新的靶点。
Exosomes are membranous nanovesicles released by most cell types from multi-vesicular endosomes. They are speculated to transfer molecules to neighboring or distant cells and modulate many physiological and pathological procedures. Exosomes released from the gastrointestinal epithelium to the basolateral side have been implicated in antigen presentation. Here, we report that luminal release of exosomes from the biliary and intestinal epithelium is increased following infection by the protozoan parasite Cryptosporidium parvum. Release of exosomes involves activation of TLR4/IKK2 signaling through promoting the SNAP23-associated vesicular exocytotic process. Downregulation of let-7 family miRNAs by activation of TLR4 signaling increases SNAP23 expression, coordinating exosome release in response to C. parvum infection. Intriguingly, exosomes carry antimicrobial peptides of epithelial cell origin, including cathelicidin-37 and beta-defensin 2. Activation of TLR4 signaling enhances exosomal shuttle of epithelial antimicrobial peptides. Exposure of C. parvum sporozoites to released exosomes decreases their viability and infectivity both in vitro and ex vivo. Direct binding to the C. parvum sporozoite surface is required for the anti-C. parvum activity of released exosomes. Biliary epithelial cells also increase exosomal release and display exosome-associated anti-C. parvum activity following LPS stimulation. Our data indicate that TLR4 signaling regulates luminal exosome release and shuttling of antimicrobial peptides from the gastrointestinal epithelium, revealing a new arm of mucosal immunity relevant to antimicrobial defense. Exosomes are secreted membranous nanovesicles produced by a variety of cells. Exosomes shuttle various molecules to transfer them to neighboring or distant cells, and have been implicated as mediators in cell-cell communications to modulate physiological and pathological procedures. Here, we report that luminal release of exosomal vesicles is an important component of Toll-like receptor 4 (TLR4)-associated gastrointestinal epithelial defense against infection by Cryptosporidium parvum, an obligate intracellular protozoan that infects gastrointestinal epithelial cells. Activation of TLR4 signaling in host epithelial cells following C. parvum infection promotes luminal release of epithelial exosomes and exosomal shuttling of antimicrobial peptides from the epithelium. By direct binding to the C. parvum surface, exosomal vesicles reveal anti-C. parvum activity. Activation of TLR4 signaling in epithelial cells after LPS stimulation also increases exosomal release and exosome-associated anti-C. parvum activity. Therefore, we speculate that TLR4-mediated exosome release may be relevant to innate mucosal immunity in general, representing a new target for therapeutic intervention for infectious diseases at the mucosal surface.
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DOI：
10.1046/j.1432-1033.2003.03719.x
发表时间：
2003-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Brandenburg, K;Wagner, F;Seydel, U
通讯作者：
Seydel, U
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
影响因子：
5.5
作者：
Chen, Xiao;Song, Chun-Hua;Yang, Ping-Chang
通讯作者：
Yang, Ping-Chang
影响因子：
4.8
作者：
Chen, XM;Splinter, PL;LaRusso, NF
通讯作者：
LaRusso, NF
影响因子：
3.7
作者：
Lovis, Pascal;Gattesco, Sonia;Regazzi, Romano
通讯作者：
Regazzi, Romano