Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections

Abstract

Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory ‘feed forward loop’. Nutrient ‘excess’ conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.

Single-cell analysis of age-related changes in leukocytes of diabetic mouse hindpaws

“…Dendritic cell-derived IL-1 has a stimulatory effect on T cell function in diabetes [ 53 ] and the reduced IL-4 signaling from DETCs may induce a net Th1 bias [ 54 ]. Impairments in neutrophil complement signaling would be consistent with the increased susceptibility to infection seen in diabetes [ 55 ]. Finally, the expression of APRIL by proinflammatory macrophages [ 56 ] and the expression of galectin by macrophages within atherosclerotic plaques [ 57 ] are consistent with the development of diabetes-related inflammation and cardiovascular disease in this model.…”

Stress, Hyperglycemia, and Insulin Resistance Correlate With Neutrophil Activity and Impact Acute Myocardial Infarction Outcomes

“…Other mechanisms on top of stress hormone activity may explain the connection between stress hyperglycemia and high neutrophil values. Acutely elevated glucose levels and IR are known to increase the expression of adhesion molecules on neutrophils and endothelial cells, aiding their migration to the inflamed myocardium [ 20 , 49 ]. Chronic glycemic status, as measured by HbA1c, showed no correlation with neutrophil activity.…”

Recent advances of hydrogels as smart dressings for diabetic wounds

“…However, in patients with diabetic wounds, high blood sugar can reduce the activity of various enzymes in neutrophils and their ability to kill bacteria on the one hand and lead to phagocytic dysfunction of macrophages and their easy conversion to a senescent phenotype on the other hand, resulting in a decreased ability to clear inflammation and prolonged chronic inflammation. 39–41…”