Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes.
Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting beta-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1beta and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.
Emre
Yalin
Y
Biotram, Universite Paris 5 Site Necker, Unité Propre de Recherche 9078, Centre National de la Recherche Scientifique, 156 Rue de Vaugirard, 75730 Paris Cedex 15, France.
Hurtaud
Corinne
C
Karaca
Melis
M
Nubel
Tobias
T
Zavala
Flora
F
Ricquier
Daniel
D
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D016207:Cytokines; D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D009569:Nitric Oxide; D013311:Streptozocin; D007371:Interferon-gamma