title: 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.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), U1151, Necker-Enfants Malades Institute (INEM) Necker Hospital, Paris, France Sorbonne Paris Cité, Université Paris Descartes, Paris, France julien.diana@inserm.fr.
authors: Julien
authors: J
authors: Diana
authors: Sorbonne Paris Cité, Université Paris Descartes, Paris, France Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Cochin Institute Cochin Hospital, Paris, France Laboratoire d'Excellence INFLAMEX, Paris, France.
authors: Agnès
authors: A
authors: Lehuen
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D016688:Mice, Inbred NOD; D020556:Neutrophil Infiltration; D010179:Pancreas / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*
chemical_list: D023063:Receptors, Interleukin-8B
keywords: autoimmunity; beta cell; diabetes; innate; neutrophil