A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity

Abstract

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.

Keywords: COVID-19; NETosis; hyperglycaemia; infection; inflammation; neutrophil; type 1 diabetes; type 2 diabetes.

Figure 1

Mediators of neutrophil dysfunction present in T1D and T2D. The microenvironment of T1D and T2D presents a complex interplay of mediators of neutrophil dysfunction. Hyperglycaemia and the formation of advanced glycation end products in the circulation and the bone marrow modify circulating neutrophils and myeloid precursors. Metabolic perturbations in lipid metabolism and increased synthesis of circulating free fatty acids further contribute to aberrant dysfunction. Resulting activated neutrophils produce pro-inflammatory mediators adding to a cycle of inflammation. Increased age further impacts neutrophil function, in addition to co-morbidities and infection, where altered neutrophil functions are previously shown e.g chronic obstructive pulmonary disease (COPD) sepsis and COVID-19. Figure created with BioRender.com.

Figure 2

Summary of changes in neutrophil function in diabetes. Neutrophils in diabetes are functionally altered, due to exposure to the diabetic microenvironment, including changes to blood glucose as well as other factors. Phagocytosis, chemotaxis, intracellular ROS production and apoptosis are reduced in diabetes, whereas extracellular ROS, cytokines and NETosis are increased. Examples of mechanisms underpinning the functional changes are also noted. extracellular superoxide dismutase (ecSOD), protein kinase C (PKC), nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), Nuclear factor-κB (NF-κB), low-density neutrophils (LDNs), G protein coupled receptor kinase-2 (GRK2). Figure created with BioRender.com.