IL-25 prevents and cures fulminant hepatitis in mice through a myeloid-derived suppressor cell-dependent mechanism

• DOI: 10.1002/hep.26446
• Publication Date: 2013-04-08T10:08:49Z
• Authors: Massimiliano Sarra; Maria Laura Cupi; Roberta Bernardini; Giulia Ronchetti; Ivan Monteleone; Marco Ranalli; Eleonora Franzè; Angelamaria Rizzo; Alfredo Colantoni; Flavio Caprioli; Marco Maggioni; Alessandra Gambac...; Maurizio Mattei; Thomas T. Macdonald; Francesco Pallone; Giovanni Monteleone
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; Settore MED/12 - GASTROENTEROLOGIA; Hepatiti; Down-Regulation; Lipopolysaccharide; Galactosamine; Hepatitis; Mice; 03 medical and health sciences; Animals; Coculture Techniques; Hepatocytes; Humans; Interleukins; Disease Models, Animal; Galactosamine; Mice; Mice, Inbred BALB C; Cell Proliferation; Receptors, Chemokine; Hepatitis; Drug-Induced Liver Injury; Concanavalin A; Down-Regulation; Myeloid Cells; Lipopolysaccharides; Interleukin-17; Male; T-Lymphocytes; Antigens, CD11b; Receptors; Concanavalin A; Animals; Humans; Hepatocyte; Myeloid Cells; Antigens; Coculture Technique; Inbred BALB C; Myeloid Cell; Cell Proliferation; Mice, Inbred BALB C; CD11b Antigen; Animal; CD11b; Interleukins; Interleukin-17; Drug-Induced Liver Injury; Interleukin; Coculture Techniques; 3. Good health; Disease Models, Animal; T-Lymphocyte; Chemokine; Disease Models; Hepatocytes; Receptors, Chemokine; Chemical and Drug Induced Liver Injury; Human

Fulminant hepatitis (FH) is a disease characterized by massive destruction of hepatocytes with severe impairment of liver function. The pathogenesis of FH is not fully understood, but hyperactivity of T cells and macrophages with excessive production of cytokines are important hallmarks of the condition. In this study, we investigated the role of interleukin (IL)−25 in FH. IL-25 expression was evaluated in patients with FH and in livers of mice with FH induced by D-galactosamine (D-Gal) and lipopolysaccharide (LPS). Mice were treated with IL-25 before D-Gal/LPS-induced FH and before or after concanavalin A (ConA)-induced FH. Mononuclear cells were isolated from livers of mice treated with or without IL-25 and analyzed for GR1+CD11b+ cells. CFSE-labeled T cells were cocultured with GR1+CD11b+ cells and their proliferation was evaluated by flow cytometry. Mice were also treated with a depleting anti-GR1 antibody before IL-25 and D-Gal/LPS administration. IL-25 was constitutively expressed in mouse and human liver and down-regulated during FH. IL-25 prevented D-Gal/LPS-induced FH and this effect was associated with increased infiltration of the liver with cells coexpressing GR1 and CD11b.

In vitro

studies showed that GR1+CD11b+ cells isolated from mice given IL-25 inhibited T-cell proliferation. Consistently,

in vivo

depletion of GR1+ cells abrogated the protective effect of IL-25 in experimental D-Gal/LPS-induced FH. IL-25 was both preventive and therapeutic in ConA-induced FH.

Conclusions

: IL-25 expression is markedly reduced during human and experimental FH. IL-25 promotes liver accumulation of GR1+CD11b+cells with immunoregulatory properties. (Hepatology 2013;58:1436–1450)