TY - JOUR
T1 - Glucose induces metabolic reprogramming in neutrophils during type 2 diabetes to form constitutive extracellular traps and decreased responsiveness to lipopolysaccharides
AU - Joshi, Manjunath B.
AU - Ahamed, Rayees
AU - Hegde, Mangala
AU - Nair, Aswathy S.
AU - Ramachandra, Lingadakai
AU - Satyamoorthy, Kapaettu
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections.
AB - Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections.
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U2 - 10.1016/j.bbadis.2020.165940
DO - 10.1016/j.bbadis.2020.165940
M3 - Article
C2 - 32827651
AN - SCOPUS:85090054850
SN - 0925-4439
VL - 1866
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 12
M1 - 165940
ER -