Zinc Deficiency Activates the IL-23/Th17 Axis to Aggravate Experimental Colitis in Mice.
Animals
Carrier Proteins
/ metabolism
Chelating Agents
/ pharmacology
Deficiency Diseases
/ immunology
Disease Models, Animal
Disease Progression
Ethylenediamines
/ pharmacology
Inflammatory Bowel Diseases
/ immunology
Interleukin-23
/ immunology
Intestinal Mucosa
/ immunology
Macrophages
/ immunology
Mice
Th17 Cells
/ immunology
Trace Elements
/ deficiency
Zinc
/ deficiency
Inflammatory bowel disease
lymphocytes
macrophages
Journal
Journal of Crohn's & colitis
ISSN: 1876-4479
Titre abrégé: J Crohns Colitis
Pays: England
ID NLM: 101318676
Informations de publication
Date de publication:
09 Jul 2020
09 Jul 2020
Historique:
pubmed:
30
11
2019
medline:
18
5
2021
entrez:
30
11
2019
Statut:
ppublish
Résumé
Patients with inflammatory bowel disease [IBD], especially Crohn's disease, often develop zinc deficiency. However, the precise mechanisms by which zinc deficiency affects IBD pathology, particularly intestinal macrophage function, remain unclear. We studied the effects of zinc deficiency on the development and progression of colitis in mice. To induce colitis, mice were treated with 2,4,6-trinitrobenzene sulphonic acid. Rag1-/- mice were then given injections of naïve CD4+CD62L+ T cells. The respective degrees of mucosal injury of mice that had received a zinc chelator (TPEN; N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) and of control mice were subsequently compared. Colonic lamina propria mononuclear cells were isolated by enzymatic digestion and were examined using flow cytometry. To generate mouse bone marrow-derived macrophages [BMDMs], bone marrow cells were stimulated with mouse macrophage-colony stimulating factor. Zinc deficiency aggravates colonic inflammation through the activation of type 17 helper T [Th17] cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory [M1] macrophages in colonic lamina propria mononuclear cells obtained from inflamed colon. Interferon-γ plus lipopolysaccharide-mediated M1 skewing alters the expression of zinc transporters in BMDMs and thereby decreases the intracellular free zinc. TPEN treatment mimicking the effects of the M1 skewing up-regulates IL-23p19 expression, which is strongly related to Th17 development. Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is closely involved in IL-23p19 induction in zinc-deficient macrophages. Zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis. This activation is controlled by subcellular distribution of interferon-regulatory factor 5.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Patients with inflammatory bowel disease [IBD], especially Crohn's disease, often develop zinc deficiency. However, the precise mechanisms by which zinc deficiency affects IBD pathology, particularly intestinal macrophage function, remain unclear. We studied the effects of zinc deficiency on the development and progression of colitis in mice.
METHODS
METHODS
To induce colitis, mice were treated with 2,4,6-trinitrobenzene sulphonic acid. Rag1-/- mice were then given injections of naïve CD4+CD62L+ T cells. The respective degrees of mucosal injury of mice that had received a zinc chelator (TPEN; N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) and of control mice were subsequently compared. Colonic lamina propria mononuclear cells were isolated by enzymatic digestion and were examined using flow cytometry. To generate mouse bone marrow-derived macrophages [BMDMs], bone marrow cells were stimulated with mouse macrophage-colony stimulating factor.
RESULTS
RESULTS
Zinc deficiency aggravates colonic inflammation through the activation of type 17 helper T [Th17] cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory [M1] macrophages in colonic lamina propria mononuclear cells obtained from inflamed colon. Interferon-γ plus lipopolysaccharide-mediated M1 skewing alters the expression of zinc transporters in BMDMs and thereby decreases the intracellular free zinc. TPEN treatment mimicking the effects of the M1 skewing up-regulates IL-23p19 expression, which is strongly related to Th17 development. Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is closely involved in IL-23p19 induction in zinc-deficient macrophages.
CONCLUSIONS
CONCLUSIONS
Zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis. This activation is controlled by subcellular distribution of interferon-regulatory factor 5.
Identifiants
pubmed: 31783404
pii: 5648054
doi: 10.1093/ecco-jcc/jjz193
doi:
Substances chimiques
Carrier Proteins
0
Chelating Agents
0
Ethylenediamines
0
Interleukin-23
0
Trace Elements
0
zinc-binding protein
0
Zinc
J41CSQ7QDS
N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
R9PTU1U29I
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
856-866Informations de copyright
Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.