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Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase–β
Yuk Yin Cheung, … , Brian C. Mansfield, Janice Y. Chou
Yuk Yin Cheung, … , Brian C. Mansfield, Janice Y. Chou
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):784-793. https://doi.org/10.1172/JCI30443.
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Research Article Immunology

Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase–β

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Abstract

Neutropenia and neutrophil dysfunction are common in many diseases, although their etiology is often unclear. Previous views held that there was a single ER enzyme, glucose-6-phosphatase–α (G6Pase-α), whose activity — limited to the liver, kidney, and intestine — was solely responsible for the final stages of gluconeogenesis and glycogenolysis, in which glucose-6-phosphate (G6P) is hydrolyzed to glucose for release to the blood. Recently, we characterized a second G6Pase activity, that of G6Pase-β (also known as G6PC), which is also capable of hydrolyzing G6P to glucose but is ubiquitously expressed and not implicated in interprandial blood glucose homeostasis. We now report that the absence of G6Pase-β led to neutropenia; defects in neutrophil respiratory burst, chemotaxis, and calcium flux; and increased susceptibility to bacterial infection. Consistent with this, G6Pase-β–deficient (G6pc3–/–) mice with experimental peritonitis exhibited increased expression of the glucose-regulated proteins upregulated during ER stress in their neutrophils and bone marrow, and the G6pc3–/– neutrophils exhibited an enhanced rate of apoptosis. Our results define a molecular pathway to neutropenia and neutrophil dysfunction of previously unknown etiology, providing a potential model for the treatment of these conditions.

Authors

Yuk Yin Cheung, So Youn Kim, Wai Han Yiu, Chi-Jiunn Pan, Hyun-Sik Jun, Robert A. Ruef, Eric J. Lee, Heiner Westphal, Brian C. Mansfield, Janice Y. Chou

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Figure 1

Generation of G6pc3–/– mice.

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Generation of G6pc3–/– mice.
               
(A) Targeting strategy. The...
(A) Targeting strategy. The wild-type allele is presented along with the targeting vector and the anticipated outcome of the recombination (targeted allele). Introns are denoted as lines, exons as boxes. Gene targeting resulted in the replacement of exons III–V with a loxP-flanked (arrowheads) neo cassette containing a diagnostic EcoRV site. The locations of the diagnostic 5′ and 3′ probes used in Southern blot analysis are shown. B, BamHI; N, NotI; R, EcoRI; RV, EcoRV; Sd, SanDI. (B) Southern blot analysis of genomic DNA from wild-type (+/+) and targeted ES (+/–) clones digested with EcoRV. (C) PCR analysis of genomic DNA of F1 intercross progeny. A wild-type locus–specific primer pair, EIVs/EVas, amplified a 440-bp fragment in the wild-type and heterozygous animals and 2 targeted locus–specific primer pairs, Neo1s/Neo2as and Neo2s/EVIas, amplified 616- and 722-bp fragments, respectively, in the heterozygous and homozygous (–/–) animals. (D) Western blot analysis of brain, muscle, and testis microsomal protein preparations (50 μg of each tissue) using an antibody against human G6Pase-β (48).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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