IDO mediates TLR9-driven protection from experimental autoimmune diabetes.
Originally predicated on the recognition of an increasing prevalence of allergy, the hygiene hypothesis was later found to accommodate the contrasting epidemiologic trends in developed countries for infectious vs autoimmune diseases. Experimentally, reduced exposure to infections will increase the risk of disease in several models of experimental autoimmunity. Although TLRs were initially considered as stimulatory molecules capable of activating early defense mechanisms against invading pathogens, emerging data suggest that they can also exert a regulatory function. In the present study, we evaluated whether TLR3 and TLR9, recognizing microbial dsDNA and CpG-containing DNA sequences, respectively, play a role in the protection from experimental autoimmune diabetes induced in C57BL/6 mice by streptozotocin. In wild-type animals, the disease was accompanied by up-regulation of IDO in pancreatic lymph nodes and would be greatly exacerbated by in vivo administration of an IDO inhibitor. Conversely, administration of a CpG-containing oligodeoxynucleotide greatly attenuated the disease in an IDO-dependent fashion. TLR9-, but not TLR3-deficient mice developed a more robust disease, an event accompanied by lack of IDO induction in pancreatic lymph nodes. Thus, our data suggest that the TLR9-IDO axis may represent a valuable target in the prevention/therapy of type 1 diabetes.
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Francesca
F
Fallarino
Claudia
C
Volpi
Teresa
T
Zelante
Carmine
C
Vacca
Mario
M
Calvitti
Maria C
MC
Fioretti
Paolo
P
Puccetti
Luigina
L
Romani
Ursula
U
Grohmann
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
C408982:CPG-oligonucleotide; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta