Rag2-deficient IL-1 Receptor Antagonist-deficient Mice Are a Novel Colitis Model in Which Innate Lymphoid Cell-derived IL-17 Is Involved in the Pathogenesis.
Il1rn(-/-) mice spontaneously develop arthritis and aortitis by an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism. Here, we show that Rag2(-/-)Il1rn(-/-) mice develop spontaneous colitis with high mortality, making a contrast to the suppression of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells (ILC3s) was observed in the colon of Rag2(-/-)Il1rn(-/-) mice. IL-17A-deficiency prolonged the survival of Rag2(-/-)Il1rn(-/-) mice, suggesting a pathogenic role of this cytokine in the development of intestinal inflammation. Although IL-17A-producing T cells were increased in Il1rn(-/-) mice, these mice did not develop colitis, because CD4(+)Foxp3(+) regulatory T cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A from ILC3s cause colitis in Rag2(-/-)Il1rn(-/-) mice in which Treg cells are absent. These observations suggest that the balance between IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the colon.
Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Aoi
A
Akitsu
Shigeru
S
Kakuta
Shinobu
S
Saijo
Yoichiro
Y
Iwakura
D000818:Animals; D003092:Colitis / Q000235:genetics* / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D004268:DNA-Binding Proteins; D020381:Interleukin-17; C499308:Rag2 protein, mouse; D017472:Receptors, Interleukin-1