Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn's Disease.
Animals
Caspase 8
/ genetics
Cell Death
Crohn Disease
/ immunology
Disease Models, Animal
Humans
Ileum
/ immunology
Interferons
/ genetics
Interleukins
/ genetics
Mice, Inbred C57BL
Mice, Knockout
Paneth Cells
/ immunology
Protein Kinases
/ genetics
STAT1 Transcription Factor
/ deficiency
Signal Transduction
Tissue Culture Techniques
Up-Regulation
Cytokine
Ileitis
Inflammatory Bowel Diseases
Necroptosis
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
25
07
2018
revised:
05
07
2019
accepted:
22
07
2019
pubmed:
29
7
2019
medline:
20
12
2019
entrez:
29
7
2019
Statut:
ppublish
Résumé
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). 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 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. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 31352002
pii: S0016-5085(19)41128-1
doi: 10.1053/j.gastro.2019.07.031
pii:
doi:
Substances chimiques
Interleukins
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
Stat1 protein, mouse
0
Interferons
9008-11-1
MLKL protein, mouse
EC 2.7.-
Protein Kinases
EC 2.7.-
Casp8 protein, mouse
EC 3.4.22.-
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1310-1322.e13Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.