Macrophages and β‐cells are responsible for CXCR2‐mediated neutrophil infiltration of the pancreas during autoimmune diabetes

Abstract

Autoimmune type 1 diabetes (T1D) development results from the interaction between pancreatic β‐cells, and the innate and the adaptive immune systems culminating with the destruction of the insulin‐secreting β‐cells by autoreactive T cells. This diabetogenic course starts during the first postnatal weeks by the infiltration of the pancreatic islets by innate immune cells and particularly neutrophils. Here, we aim to determine the cellular and molecular mechanism leading to the recruitment of this neutrophils in the pancreatic islets of non‐obese diabetic (NOD) mice. Here, we show that neutrophil recruitment in the pancreatic islets is controlled by inflammatory macrophages and β‐cells themselves. Macrophages and β‐cells produce the chemokines CXCL1 and CXCL2, recruiting CXCR2‐expressing neutrophils from the blood to the pancreatic islets. We further show that pancreatic macrophages secrete IL‐1β‐inducing CXCR2 ligand production by the β‐cells. Finally, the blockade of neutrophil recruitment at early ages using CXCR2 antagonist dampens the diabetogenic T‐cell response and the later development of autoimmune diabetes, supporting the therapeutic potential of this approach. image This study reveals the interaction between inflammatory macrophages and β‐cells leading to the recruitment of diabetogenic neutrophils in the pancreas of neonatal mice via CXCR2/CXCR2 ligands. Inhibition of CXCR2 reduces the diabetogenic T‐cell response, insulitis, and incidence of diabetes. In young NOD mice, CXCR2 + ‐neutrophils are recruited from the blood into the pancreatic islets and not in the two non‐diabetes prone C57BL/6 and BALB/c mice. The two CXCR2 ligands, CXCL1 and CXCL2, are secreted in the pancreatic islets from the young and not from the adult NOD mice or the two non‐diabetes prone mice. The pancreatic β‐cells are the main source of CXCL1 and CXCL2 in the pancreatic islets of young NOD mice. The production of CXCL1 and CXCL2 by the β‐cells is induced by IL‐1b‐producing macrophages infiltrating the pancreatic islets of young NOD mice. The early blockage of neutrophil recruitment using CXCR2 antagonist reduces the insulitis, the effector activity of diabetogenic CD8 T cells, and the development of autoimmune diabetes in NOD mice.