Remote Control of Intestinal Stem Cell Activity by Haemocytes in Drosophila.
Remote Control of Intestinal Stem Cell Activity by Haemocytes in Drosophila.
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DOI：
10.1371/journal.pgen.1006089
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发表时间：
2016-05
期刊：
影响因子：
4.5
通讯作者：
Lemaitre B
中科院分区：
文献类型：
--
作者：
Chakrabarti S;Dudzic JP;Li X;Collas EJ;Boquete JP;Lemaitre B
JAK/STAT信号通路是后生动物发育和免疫调节的关键信号通路。与哺乳动物中的多种组合JAK/STAT途径不同，果蝇中仅存在一种典型的JAK/STAT途径。它由三种未配对家族（Upd）的分泌蛋白激活：Upd 1，Upd 2和Upd 3。虽然许多研究已经建立了JAK/STAT激活和组织损伤之间的联系，激活的模式和该途径在果蝇系统性免疫反应中的确切功能仍不清楚。在这项研究中，我们使用upd 2和upd 3中的突变来研究JAK/STAT通路在全身免疫应答中的作用。我们的研究表明，血细胞表达三种upd基因，并且损伤通过血细胞中的JNK途径显著诱导upd 3的表达，这反过来激活脂肪体和肠道中的JAK/STAT途径。令人惊讶的是，损伤后血细胞释放的Upd 3可以远程刺激干细胞增殖和肠中Drosomycin样基因的表达。我们的研究结果还表明，一定水平的肠上皮更新是需要最佳的生存败血性损伤。虽然血细胞衍生的Upd促进肠干细胞活化和脓毒性损伤后的存活，但血细胞在口腔细菌感染后被用于上皮更新。我们的研究还表明，肠上皮更新是敏感的侮辱管腔和血腔。它还揭示了血细胞释放Upds协调多个组织中的伤口愈合程序，包括肠道，一个完整性对苍蝇生存至关重要的器官。先天免疫是抵抗入侵生物的主要防线。这种反应始于宿主受体对微生物特异性分子如脂多糖和肽聚糖的感应。后生动物还可以识别与组织损伤和创伤相关的信号，然后激活参与组织修复或炎症的特定途径。先前的研究表明JAK/STAT激活与果蝇的组织修复之间存在联系，但该途径的激活模式和确切功能仍不清楚。在这篇文章中，我们分析了JAK/STAT信号通路在果蝇抗损伤中的作用。我们表明，这一途径有助于苍蝇抗创伤和细菌感染。从机制上讲，损伤诱导血细胞产生称为Unpaireds的分泌分子，然后激活脂肪体（相当于脊椎动物肝脏的器官）和肠道中的JAK/STAT通路。我们研究中最令人惊讶的发现之一是，从血细胞中释放的Unpaireds可以远程刺激肠道干细胞增殖。因此，我们发现了循环血细胞和肠道干细胞增殖之间意想不到的相互作用，有助于受伤后的苍蝇生存。
The JAK/STAT pathway is a key signaling pathway in the regulation of development and immunity in metazoans. In contrast to the multiple combinatorial JAK/STAT pathways in mammals, only one canonical JAK/STAT pathway exists in Drosophila. It is activated by three secreted proteins of the Unpaired family (Upd): Upd1, Upd2 and Upd3. Although many studies have established a link between JAK/STAT activation and tissue damage, the mode of activation and the precise function of this pathway in the Drosophila systemic immune response remain unclear. In this study, we used mutations in upd2 and upd3 to investigate the role of the JAK/STAT pathway in the systemic immune response. Our study shows that haemocytes express the three upd genes and that injury markedly induces the expression of upd3 by the JNK pathway in haemocytes, which in turn activates the JAK/STAT pathway in the fat body and the gut. Surprisingly, release of Upd3 from haemocytes upon injury can remotely stimulate stem cell proliferation and the expression of Drosomycin-like genes in the intestine. Our results also suggest that a certain level of intestinal epithelium renewal is required for optimal survival to septic injury. While haemocyte-derived Upd promotes intestinal stem cell activation and survival upon septic injury, haemocytes are dispensable for epithelium renewal upon oral bacterial infection. Our study also indicates that intestinal epithelium renewal is sensitive to insults from both the lumen and the haemocoel. It also reveals that release of Upds by haemocytes coordinates the wound-healing program in multiple tissues, including the gut, an organ whose integrity is critical to fly survival. Innate immunity acts as the primary line of defense to overcome invading organisms. This response starts through sensing of microbe-specific molecules such as lipopolysaccharide and peptidoglycan by host receptors. Metazoans can also recognize signals that are associated with tissue damage and wounding, to then activate specific pathways involved in tissue repair or inflammation. Previous studies have suggested a link between JAK/STAT activation and tissue repair in Drosophila, but the mode of activation and the precise function of this pathway remain unclear. In this article, we analyze the role of the JAK/STAT pathway in the resistance to wounding in Drosophila. We show that this pathway contributes to fly resistance to wounding and bacterial infection. Mechanistically, injury induces the production of secreted molecules called Unpaireds by blood cells, which then activate the JAK/STAT pathway in the fat body (an organ equivalent to the vertebrate liver) and in the gut. One of the most surprising findings of our study is that Unpaireds released from blood cells can remotely stimulate intestinal stem cell proliferation. Thus, we uncover an unexpected interaction between circulating blood cells and intestinal stem cell proliferation that contributes to fly survival after injury.