Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice.
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.


CONCLUSIONS
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.
Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Aki
A
Ikeda
Nobuhiro
N
Aoki
Masahiro
M
Kido
Satoru
S
Iwamoto
Hisayo
H
Nishiura
Ryutaro
R
Maruoka
Tsutomu
T
Chiba
Norihiko
N
Watanabe
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D054367:Receptors, CXCR3 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D013934:Thymectomy; D000098815:T-bet Transcription Factor
D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D020382:Interleukin-18; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054367:Receptors, CXCR3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma