Intestinal proinflammatory macrophages induce a phenotypic switch in interstitial cells of Cajal.
Animals
Colon
/ metabolism
Enterocolitis
/ genetics
Female
Hirschsprung Disease
/ metabolism
Humans
Interstitial Cells of Cajal
/ metabolism
Macrophage Activation
Macrophages
Male
Mice
Mice, Knockout
MicroRNAs
/ genetics
NF-kappa B
/ genetics
Receptor, Endothelin B
/ genetics
Signal Transduction
Tumor Necrosis Factor-alpha
/ genetics
Gastroenterology
Inflammatory bowel disease
Macrophages
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
10
12
2018
accepted:
13
08
2020
pubmed:
19
8
2020
medline:
17
2
2021
entrez:
19
8
2020
Statut:
ppublish
Résumé
Interstitial cells of Cajal (ICCs) are pacemaker cells in the intestine, and their function can be compromised by loss of C-KIT expression. Macrophage activation has been identified in intestine affected by Hirschsprung disease-associated enterocolitis (HAEC). In this study, we examined proinflammatory macrophage activation and explored the mechanisms by which it downregulates C-KIT expression in ICCs in colon affected by HAEC. We found that macrophage activation and TNF-α production were dramatically increased in the proximal dilated colon of HAEC patients and 3-week-old Ednrb-/- mice. Moreover, ICCs lost their C-KIT+ phenotype in the dilated colon, resulting in damaged pacemaker function and intestinal dysmotility. However, macrophage depletion or TNF-α neutralization led to recovery of ICC phenotype and restored their pacemaker function. In isolated ICCs, TNF-α-mediated phosphorylation of p65 induced overexpression of microRNA-221 (miR-221), resulting in suppression of C-KIT expression and pacemaker currents. We also identified a TNF-α/NF-κB/miR-221 pathway that downregulated C-KIT expression in ICCs in the colon affected by HAEC. These findings suggest the important roles of proinflammatory macrophage activation in a phenotypic switch of ICCs, representing a promising therapeutic target for HAEC.
Identifiants
pubmed: 32809970
pii: 126584
doi: 10.1172/JCI126584
pmc: PMC7685750
doi:
pii:
Substances chimiques
EDNRB protein, human
0
EDNRB protein, mouse
0
MIRN221 microRNA, human
0
MIRN221 microRNA, mouse
0
MicroRNAs
0
NF-kappa B
0
Receptor, Endothelin B
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6443-6456Références
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