Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes.
Aire-deficient mice are a model of the human monogenic disorder autoimmune polyendocrine syndrome type I (APS I) characterized by a progressive autoimmune destruction of multiple endocrine glands such as the adrenal cortex, the parathyroids and the beta-cells of the pancreas. The disease is caused by mutations in the autoimmune regulator (AIRE) gene, a putative transcription factor expressed in thymic medullary epithelial cells and in antigen-presenting cells of the myeloid lineage in peripheral lymphoid organs. As Aire(-/-) mice do not spontaneously develop endocrinopathies, we wanted to evaluate the autoimmune multiple low-dose streptozotocin (MLDSTZ) diabetes model in Aire(-/-) mice. Surprisingly, Aire heterozygote mice were most susceptible to MLDSTZ-induced diabetes, whereas Aire(-/-) mice displayed an intermediate sensitivity to diabetes. Furthermore, Aire(-/-) macrophages produced higher levels of TNF-alpha and lower levels of IL-10 following streptozotocin stimulation, and Aire(-/-) mice developed a higher frequency of islet cells autoantibodies as a sign of increased activation. However, the number of islet infiltrating F4/80(+) Aire(-/-) macrophages was significantly decreased which was attributed to an increased susceptibility to streptozotocin cytotoxicity of Aire(-/-) macrophages. In conclusion, Aire(-/-) macrophages display an increased activation after STZ stimuli, but suffer from increased susceptibility to STZ cytotoxicity. These results support an important function of Aire in the control of peripheral tolerance through myeloid antigen-presenting cells.
Hässler
S
S
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
Peltonen
L
L
Sandler
S
S
Winqvist
O
O
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000503:physiopathology; D013154:Spleen / Q000276:immunology; D013311:Streptozocin / Q000009:adverse effects; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000096927:AIRE Protein
D013311:Streptozocin; D014157:Transcription Factors; D000096927:AIRE Protein