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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 Article has an altmetric score of 5

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 3

Analysis of myeloid functions.

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Analysis of myeloid functions.
(A) Neutrophil counts in 3-week-old (n = ...
(A) Neutrophil counts in 3-week-old (n = 8) and 6-week-old (n = 12) wild-type and G6pc3–/– mice. (B) Total peritoneal neutrophil counts in 6- to 7-week-old wild-type (n = 15) and G6pc3–/– (n = 16) mice challenged with thioglycollate. (C) Hema 3–stained cytospins of peritoneal neutrophils obtained from 7-week-old wild-type and G6pc3–/– mice. (D) Western blot analysis of protein extracts of peritoneal neutrophils (50 μg/lane) from 6- to 7-week-old wild-type and G6pc3–/– mice using antibodies against gelatinase, Gr-1, or β-actin. (E) Neutrophil respiratory burst activity. Results represent triplicate determinations using peritoneal neutrophils from 6- to 7-week-old wild-type (open circles) or G6pc3–/– (filled circles) mice. RLU, relative light unit. Values are mean ± SEM. *P < 0.03; †P < 0.0005 versus wild-type.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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