Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency.
Biomarkers
Cytokines
/ metabolism
Disease Management
Disease Susceptibility
Glucose-6-Phosphatase
/ genetics
Hematopoietic Stem Cell Transplantation
Humans
Inflammation Mediators
/ metabolism
Inflammatory Bowel Diseases
/ etiology
Loss of Function Mutation
Neutrophil Activation
/ genetics
Neutrophils
/ immunology
HSCT
cell death
inflammatory bowel disease
neutrophil
transplant
Journal
Journal of leukocyte biology
ISSN: 1938-3673
Titre abrégé: J Leukoc Biol
Pays: England
ID NLM: 8405628
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
28
08
2020
received:
09
12
2019
accepted:
29
08
2020
pubmed:
16
9
2020
medline:
31
8
2021
entrez:
15
9
2020
Statut:
ppublish
Résumé
The glucose-6-phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss-of-function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra-hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony-stimulating factor (G-CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency-associated IBD. G6PC3 deficiency was associated with early-onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G-CSF treatment. In vitro studies on the patients' blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL-8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency-associated IBD refractory to immune suppressants.
Identifiants
pubmed: 32930428
doi: 10.1002/JLB.5AB1219-699RR
doi:
Substances chimiques
Biomarkers
0
Cytokines
0
Inflammation Mediators
0
Glucose-6-Phosphatase
EC 3.1.3.9
G6PC3 protein, human
EC 3.1.3.9.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1147-1154Subventions
Organisme : Medical Research Council
ID : MR/N001427/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202865/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.
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