Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency

Anu Goenka, John A Doherty, Tariq Al-Farsi, Christopher Jagger, Siddhartha Banka, Edmund Cheesman, Andrew Fagbemi, Stephen M Hughes, Robert F Wynn, Tracy Hussell, Peter D Arkwright*

*Corresponding author for this work

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Abstract

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 G-CSF and hematopoietic stem cell transplantation (HSCT) were investigated in four 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.
Original languageEnglish
Number of pages8
JournalJournal of Leukocyte Biology
Early online date15 Sep 2020
DOIs
Publication statusE-pub ahead of print - 15 Sep 2020

Keywords

  • neutrophil
  • inflammatory bowel disease
  • HSCT
  • transplant
  • cell death

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    Goenka, A., Doherty, J. A., Al-Farsi, T., Jagger, C., Banka, S., Cheesman, E., Fagbemi, A., Hughes, S. M., Wynn, R. F., Hussell, T., & Arkwright, P. D. (2020). Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency. Journal of Leukocyte Biology. https://doi.org/10.1002/JLB.5AB1219-699RR