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Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn's Disease.
Gastroenterology ( IF 25.7 ) Pub Date : 2019-07-25 , DOI: 10.1053/j.gastro.2019.07.031 Claudia Günther 1 , Barbara Ruder 1 , Iris Stolzer 1 , Heidrun Dorner 1 , Gui-Wei He 1 , Mircea Teodor Chiriac 1 , Konrad Aden 2 , Anne Strigli 3 , Miriam Bittel 1 , Sebastian Zeissig 3 , Philip Rosenstiel 2 , Raja Atreya 1 , Markus F Neurath 1 , Stefan Wirtz 1 , Christoph Becker 1
Gastroenterology ( IF 25.7 ) Pub Date : 2019-07-25 , DOI: 10.1053/j.gastro.2019.07.031 Claudia Günther 1 , Barbara Ruder 1 , Iris Stolzer 1 , Heidrun Dorner 1 , Gui-Wei He 1 , Mircea Teodor Chiriac 1 , Konrad Aden 2 , Anne Strigli 3 , Miriam Bittel 1 , Sebastian Zeissig 3 , Philip Rosenstiel 2 , Raja Atreya 1 , Markus F Neurath 1 , Stefan Wirtz 1 , Christoph Becker 1
Affiliation
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BACKGROUND & AIMS
Interferon lambda (IFNL) is expressed at high levels by intestinal epithelial cells (IECs) and mucosal immune cells in response to infection and inflammation. We investigated whether IFNL might contribute to pathogenesis of Crohn's disease (CD).
METHODS
We obtained serum samples and terminal ileum biopsies from 47 patients with CD and 16 healthy individuals (controls). We measured levels of IFNL by enzyme-linked immunosorbent assay and immunohistochemistry and location of expression by confocal microscopy. Activation of IFNL signaling via STAT1 was measured in areas of no, mild, moderate, and severe inflammation and correlated with Paneth cell homeostasis and inflammation. IFNL expression and function were studied in wild-type mice and mice with intestinal epithelial cell-specific (ΔIEC) disruption or full-body disruption of specific genes (Mlkl-/-, Stat1ΔIEC, Casp8ΔIEC, Casp8ΔIECRipk3-/-, Casp8ΔIECTnfr-/-, Casp8ΔIECMlkl-/-, and Nod2-/- mice). Some mice were given tail vein injections of a vector encoding a secreted form of IFNL. Intestinal tissues were collected from mice and analyzed by immunohistochemistry and immunoblots. We generated 3-dimensional small intestinal organoids from mice and studied the effects of IFNL and inhibitors of STAT-signaling pathway.
RESULTS
Patients with CD had significant increases in serum and ileal levels of IFNL compared with controls. Levels of IFNL were highest in ileum tissues with severe inflammation. High levels of IFNL associated with a reduced number of Paneth cells and increased cell death at the crypt bottom in inflamed ileum samples. Intestinal tissues from the ileum of wild-type mice injected with a vector expressing IFNL had reduced numbers of Paneth cells. IFNL-induced death of Paneth cells in mice did not occur via apoptosis, but required Mixed Lineage Kinase Domain Like (MLKL) and activation of Signal transducer and activator of transcription 1 (STAT1). In organoids, inhibitors of Janus kinase (JAK) signaling via STAT1 (glucocorticoids, tofacitinib, or filgotinib) reduced expression of proteins that mediate cell death and prevented Paneth cell death.
CONCLUSIONS
Levels of IFNL are increased in serum and inflamed ileal tissues from patients with CD and associated with a loss of Paneth cells. Expression of a secreted form of IFNL in mice results in loss of Paneth cells from intestinal tissues, via STAT1 and MLKL, controlled by caspase 8. Strategies to reduce IFNL or block its effects might be developed for treatment of patients with CD affecting the terminal ileum.
中文翻译：
干扰素Lambda通过STAT1信号促进小鼠Paneth细胞死亡，并在克罗恩病患者发炎的回肠组织中增加。
背景与目的响应于感染和炎症反应，肠上皮细胞（IEC）和粘膜免疫细胞高水平表达干扰素λ（IFNL）。我们调查了IFNL是否可能导致克罗恩病（CD）的发病机理。方法我们从47位CD患者和16位健康个体（对照）中获得了血清样本和回肠末端活检。我们通过酶联免疫吸附测定和免疫组化测定了IFNL的水平，并通过共聚焦显微镜检测了表达的位置。在无，轻度，中度和严重炎症区域测量了通过STAT1激活的IFNL信号，并与Paneth细胞稳态和炎症相关。在野生型小鼠和肠道上皮细胞特异性（ΔIEC）破坏或特定基因（Mlkl-/-，Stat1ΔIEC，Casp8ΔIEC，Casp8ΔIECRipk3-/-，Casp8ΔIECTnfr-/-的全身破坏）的小鼠中研究了IFNL的表达和功能。 ，Casp8ΔIECMlk1-/-和Nod2-/-小鼠）。给一些小鼠尾静脉注射编码分泌形式的IFNL的载体。从小鼠收集肠组织，并通过免疫组织化学和免疫印迹进行分析。我们从小鼠体内产生了三维小肠类器官，并研究了IFNL和STAT信号通路抑制剂的作用。结果与对照组相比，CD患者血清和回肠的IFNL水平显着增加。在严重炎症的回肠组织中，IFNL水平最高。高水平的IFNL与发炎的回肠样品中Paneth细胞数量减少和隐窝底部细胞死亡增加相关。注射表达IFN的载体的野生型小鼠回肠的肠道组织中Paneth细胞的数量减少了。IFNL诱导的Paneth细胞在小鼠中的死亡不是通过细胞凋亡发生的，而是需要混合谱系激酶结构域类似物（MLKL）以及信号转导子和转录激活子1（STAT1）激活。在类器官中，通过STAT1进行的Janus激酶（JAK）信号抑制剂（糖皮质激素，托法替尼或filgotinib）减少了介导细胞死亡并阻止Paneth细胞死亡的蛋白质的表达。结论患有CD且与Paneth细胞丢失有关的血清和发炎的回肠组织中IFNL的水平升高。
更新日期：2019-11-18
中文翻译：
干扰素Lambda通过STAT1信号促进小鼠Paneth细胞死亡，并在克罗恩病患者发炎的回肠组织中增加。
背景与目的响应于感染和炎症反应，肠上皮细胞（IEC）和粘膜免疫细胞高水平表达干扰素λ（IFNL）。我们调查了IFNL是否可能导致克罗恩病（CD）的发病机理。方法我们从47位CD患者和16位健康个体（对照）中获得了血清样本和回肠末端活检。我们通过酶联免疫吸附测定和免疫组化测定了IFNL的水平，并通过共聚焦显微镜检测了表达的位置。在无，轻度，中度和严重炎症区域测量了通过STAT1激活的IFNL信号，并与Paneth细胞稳态和炎症相关。在野生型小鼠和肠道上皮细胞特异性（ΔIEC）破坏或特定基因（Mlkl-/-，Stat1ΔIEC，Casp8ΔIEC，Casp8ΔIECRipk3-/-，Casp8ΔIECTnfr-/-的全身破坏）的小鼠中研究了IFNL的表达和功能。 ，Casp8ΔIECMlk1-/-和Nod2-/-小鼠）。给一些小鼠尾静脉注射编码分泌形式的IFNL的载体。从小鼠收集肠组织，并通过免疫组织化学和免疫印迹进行分析。我们从小鼠体内产生了三维小肠类器官，并研究了IFNL和STAT信号通路抑制剂的作用。结果与对照组相比，CD患者血清和回肠的IFNL水平显着增加。在严重炎症的回肠组织中，IFNL水平最高。高水平的IFNL与发炎的回肠样品中Paneth细胞数量减少和隐窝底部细胞死亡增加相关。注射表达IFN的载体的野生型小鼠回肠的肠道组织中Paneth细胞的数量减少了。IFNL诱导的Paneth细胞在小鼠中的死亡不是通过细胞凋亡发生的，而是需要混合谱系激酶结构域类似物（MLKL）以及信号转导子和转录激活子1（STAT1）激活。在类器官中，通过STAT1进行的Janus激酶（JAK）信号抑制剂（糖皮质激素，托法替尼或filgotinib）减少了介导细胞死亡并阻止Paneth细胞死亡的蛋白质的表达。结论患有CD且与Paneth细胞丢失有关的血清和发炎的回肠组织中IFNL的水平升高。
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