These authors contributed equally to this work.
Autoimmune, Cholestatic and Biliary Disease
Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice
Article first published online: 28 MAY 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 1, pages 224–236, July 2014
How to Cite
Ikeda, A., Aoki, N., Kido, M., Iwamoto, S., Nishiura, H., Maruoka, R., Chiba, T. and Watanabe, N. (2014), Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice. Hepatology, 60: 224–236. doi: 10.1002/hep.27087
The Center for Innovation in Immunoregulative Technology and Therapeutics is supported, in part, by the Special Coordination Funds for Promoting Science and Technology of the Japanese Government and, in part, by Astellas Pharma Inc. in the Formation of the Innovation Center for Fusion of Advanced Technologies Program. This work is partially supported by Grants-in-Aid for Scientific Research (20390207, 21229009, and 23590973) from the Japan Society for the Promotion of Science, a Health and Labor Sciences Research Grant for Research on Intractable Diseases, and Research on Hepatitis from the Ministry of Health, Labor and Welfare, Japan, Grants-in-Aid for Research by The Kato Memorial Trust for Nambyo Research, and The Waksman Foundation of Japan.
Potential conflict of interest: Nothing to report.
- Issue published online: 26 JUN 2014
- Article first published online: 28 MAY 2014
- Accepted manuscript online: 23 FEB 2014 03:24AM EST
- Manuscript Accepted: 19 FEB 2014
- Manuscript Received: 2 AUG 2013
Clinical manifestations of autoimmune hepatitis (AIH) range from mild chronic to acute, sometimes fulminant hepatitis. However, it is unknown how the progression to fatal hepatitis occurs. We developed a mouse model of fatal AIH by inducing a concurrent loss of forkhead box P3+ regulatory T cells and programmed cell death-1 (PD-1)-mediated signaling. In this model, dysregulated follicular helper T cells in the spleen are responsible for the induction, and the C-C chemokine receptor 6/C-C chemokine ligand 20 axis is crucial for the migration of these T cells into the liver. Using this fatal AIH model, we aimed to clarify key molecules triggering fatal AIH progression. During progression, T-bet together with interferon (IFN)-γ and C-X-C chemokine receptor (CXCR)3 were highly expressed in the inflamed liver, suggesting helper T (Th)1-type inflammation. T cells that dominantly expanded in the spleen and the inflamed liver were CXCR3-expressing CD8+ T cells; depletion of these CD8+ T cells suppressed AIH progression. Expression of one CXCR3 ligand, chemokine (C-X-C motif) ligand (CXCL)9, was elevated in the liver. CXCL9-expressing macrophages/Kupffer cells were colocalized with infiltrating T cells, and in vivo administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of interleukin (IL)-18, but not IL-1β, were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18. In vivo administration of anti-IL-18R suppressed the increase of splenic CXCR3+ T cells and the progression to fatal AIH. Moreover, tumor necrosis factor alpha, but not IFN-γ, was involved in up-regulating CXCL9 in the liver and for increased serum levels of IL-18. Conclusion: These data suggest that, in our mouse model, fatal progression of AIH is mediated by IL-18-dependent differentiation of T cells into Th1 cells and effector T cells, respectively, and that CXCR3-CXCL9 axis-dependent migration of those T cells is crucial for fatal progression. (Hepatology 2014;60:224–236)