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.

Group B Streptococcus Adaptation Promotes Survival in a Hyperinflammatory Diabetic Wound Environment

“…Analysis of the host response in diabetic vs non-diabetic animals that were inoculated with PBS revealed upregulation of genes involving epithelial mesenchymal transition, interferon alpha response, inflammation and adipogenesis ( Supplementary Fig 1 ). These data support current literature on the improper immune response associated with diabetes and hyper-inflammation of diabetic wounds (1, 42, 43).…”

“…A hallmark characteristic of diabetic individuals is an altered neutrophil response due to persistent hyperglycemia. Neutrophils from diabetic individuals are often pro-inflammatory, exhibiting increased neutrophil extracellular trap (NET) formation, pro-inflammatory cytokine production and extracellular ROS generation (1, 57). Additionally, decreased apoptosis, neutrophil migration and intracellular ROS production have been shown in diabetic individuals, leading to impaired bacterial killing (58).…”

NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease

“…A number of studies have assessed neutrophil function and count in T1DM, with diverging results (10). However, the current hypothesis is that patients with long-term T1DM most likely have some degree of neutrophil dysfunction (30)(31)(32)(33). Whether this is due to the hyperglycemia per se, or a primary neutrophil defect is not known (31,34).…”

Mucormycosis in the COVID-19 Environment: A Multifaceted Complication

“…Neutrophils migrate toward fungal pathogens and mediate fungal killing through phagocytosis, oxidative stress, and neutrophil extracellular traps (NETs) ( Urban and Nett, 2019 ). Neutrophil functions such as migration, oxidative burst, and NET formation are modified in diabetic subjects, leading to decreased clearance of fungal pathogens ( Dowey et al., 2021 ). Certain fungi such as Rhizopus can metabolize ketone bodies present in the patients with DKA resulting in angioinvasion, thrombosis, and ischemic tissue necrosis ( Katragkou et al., 2014 ; Lin et al., 2017 ).…”

“…While the association of neutropenia with COVID-19 is not well established, diabetes is typically accompanied by neutropenia ( Alba-Loureiro et al., 2007 ). Additionally, functions of neutrophils including phagocytosis, migration, and intracellular reactive oxygen species (ROS) generation are impaired in hyperglycemic conditions ( Dowey et al., 2021 ). The modulation of neutrophil functions in DKA remains a subject of investigation.…”