Complete Deficiency of Leukocyte Glucose-6-Phosphate Dehydrogenase with Defective Bactericidal Activity

Cooper, M. Robert; DeChatelet, Lawrence R.; McCall, Charles E.; Via, Mariano F. La; Spurr, Charles L.; Baehner, Robert L.

doi:10.1172/jci106871

Cited by 185 publications

(65 citation statements)

References 42 publications

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“…Also, mononuclear cells from G6PD-deficient patients secret fewer proinflammatory cytokines than those from normal subjects (43). Furthermore, severe G6PD deficiency resembles chronic granulomatous disease in that granulocytes from G6PD-deficient patients have a defect in the respiratory burst responsible for killing bacteria in granulocytes (44)(45)(46). In line with these findings, in the present work, we report that increased G6PD expression in macrophages promotes proinflammatory signaling cascades by augmenting oxidative stress.…”

Section: Discussionsupporting

confidence: 84%

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

et al. 2013

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Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that regulates cellular redox potential. In this study, we demonstrate that macrophage G6PD plays an important role in the modulation of proinflammatory responses and oxidative stress. The G6PD levels in macrophages in the adipose tissue of obese animals were elevated, and G6PD mRNA levels positively correlated with those of proinflammatory genes. Lipopolysaccharide (LPS) and free fatty acids, which initiate proinflammatory signals, stimulated macrophage G6PD. Overexpression of macrophage G6PD potentiated the expression of proinflammatory and prooxidative genes responsible for the aggravation of insulin sensitivity in adipocytes. In contrast, when macrophage G6PD was inhibited or suppressed via chemical inhibitors or small interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased activation of the p38 mitogen-activated protein kinase (MAPK) and NF-B pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals.

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Section: Discussionsupporting

confidence: 84%

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

et al. 2013

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“…Studies on human G6PD deficiencies have suggested that G6PD would contribute to mediating immune cell functions (47)(48)(49). Severe human G6PD deficiency causes a chronic granulomatous disease with increased susceptibility to infections because of a defect in hydrogen peroxide production by granulocytes (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Severe human G6PD deficiency causes a chronic granulomatous disease with increased susceptibility to infections because of a defect in hydrogen peroxide production by granulocytes (47,48). Additionally, monocyte-derived macrophages from subjects with G6PD-deficiency exhibit reduced secretion of inflammatory cytokines such as TNFa and IL-1b (49).…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

et al. 2016

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Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PDmut) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PDmut mice. In diet-induced obesity (DIO), the adipose tissue of G6PDmut mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PDmut mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PDmut bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses.

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“…[21][22][23][24] The few patients with G6PD deficiency and recurrent catalase-positive infections reported in the literature had undetectable leukocyte G6PD activity. 14,15,25,26 In an earlier report, 3 a proposal to modify the classification of G6PD deficiency according to the enzyme level in RBC was made, distinguishing between complete absence of G6PD in erythrocytes, and severe yet incomplete RBC G6PD deficiency. A subsequent study supported this proposal based on the finding that when erythrocyte G6PD activity is completely absent, the PMN level is significantly lower than the normal control, whereas in individuals with severe (<10% of normal) but incomplete erythrocyte G6PD deficiency, the PMN G6PD level is not different from the normals.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 In this study, the G6PD levels of PMNs isolated from 20 healthy individuals with severe RBC G6PD deficiency and 20 normal controls were determined, and these were correlated with their in vitro bactericidal activity against catalase-positive and catalase-negative microorganisms and their ability to reduce NBT.…”

mentioning

confidence: 99%

Bactericidal Activity of Polymorphonuclear Neutrophils in Individuals Severely Deficient in Glucose-6-Phosphate Dehydrogenase

et al. 1998

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Complete Deficiency of Leukocyte Glucose-6-Phosphate Dehydrogenase with Defective Bactericidal Activity

Cited by 185 publications

References 42 publications

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

Bactericidal Activity of Polymorphonuclear Neutrophils in Individuals Severely Deficient in Glucose-6-Phosphate Dehydrogenase

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