Neutrophils in type 1 diabetes

Abstract

Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin-producing pancreatic β-cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β-cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil-derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell-cell interactions with other immune and non-immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes.

Keywords: Immune cells; Neutrophils; Type 1 diabetes.

Figure 1

Neutrophil‐derived multiple effector molecules. During the process of maturation or on stimuli activation, neutrophils can express and/or release numerous cytotoxic substances. Three categories of granules, including azurophil granules, specific granules and gelatinase granules, are discharged during the degranulation process and are recognized as the basis content of their enzyme. Apart from these classical granules, neutrophils contain highly mobilizable secretory vesicles that serve as a reservoir primarily for plasma membrane receptors. Simultaneously with their degranulation, the initiation of nicotinamide adenine dinucleotide phosphate oxidase activity (a part of the cellular respiratory burst) in neutrophils occurs, and then various reactive oxygen species (ROS) are generated. Furthermore, neutrophils can produce numerous cytokines, which are considered to be the most critical effectors because of their vast and diverse of biological activities. In addition, neutrophils can be activated to undergo NETosis (a novel form of cell death) and extrude extracellular fibrillary networks termed neutrophil extracellular traps (NETs). APRIL, a proliferation‐inducing ligand; BAFF, B cell activating factor; BPIP, bactericidal permeability increasing protein; DNA, deoxyribonucleic acid; EGF, epidermal growth factor; G‐CSF, granulocyte colony stimulating factor; HB‐EGF, heparin binding epidermal growth factor; HGF, hepatocyte growth factor; IL‐1RA, interleukin‐1 receptor antagonist; MIF, macrophage migration inhibitory factor; PBEF, pre‐B cell colony enhancing factor; RANKL, receptor activator for nuclear factor‐κ B ligand; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; TRAIL, tumor necrosis factor‐related apoptosis inducing factor.

Figure 2

Neutrophils and type 1 diabetes. The mechanism of the initiation and pathogenesis of type 1 diabetes still remains unclear. Physiological β‐cell death was considered as an essential trigger in the development of the disease, which can recruit and activate immune cells, particularly neutrophils, to infiltrate in pancreatic islets. In the pancreas, neutrophils can release cathelicidin‐related antimicrobial peptide (CRAMP), the process of which is activated by deoxyribonucleic acid (DNA)‐specific immunoglobulin G secreted from B‐1a cells. These immunoglobulin G and CRAMP peptide complex, together with β‐cell debris like self‐deoxyribonucleic acid, can induce plasmacytoid dendritic cells to produce interferon‐α. The aforementioned cross‐talk between these immune cells is required to induce diabetogenic T‐cell response and then leads to the initiation of type 1 diabetes. Additionally, interaction between neutrophils and other non‐immune cells, such as platelets in the blood or endothelial cells on the blood vessels, is supposed to play essential roles in diabetic microvascular and macrovascular complications. Conversely, neutrophils can be activated and impaired by metabolic changes in type 1 diabetes patients. AGEs, advanced glycation end‐products; IFN, interferon.