title: The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice.
abstract: The mechanisms responsible for the evolution of steatosis towards NASH (non-alcoholic steatohepatitis) and fibrosis are not completely defined. In the present study we evaluated the role of CD4(+) T-helper (Th) cells in this process. We analysed the infiltration of different subsets of CD4(+) Th cells in C57BL/6 mice fed on a MCD (methionine choline-deficient) diet, which is a model reproducing all phases of human NASH progression. There was an increase in Th17 cells at the beginning of NASH development and at the NASH-fibrosis transition, whereas levels of Th22 cells peaked between the first and the second expansion of Th17 cells. An increase in the production of IL (interleukin)-6, TNFα (tumour necrosis factor α), TGFβ (transforming growth factor β) and CCL20 (CC chemokine ligand 20) accompanied the changes in Th17/Th22 cells. Livers of IL-17(-/-) mice were protected from NASH development and characterized by an extensive infiltration of Th22 cells. In vitro, IL-17 exacerbated the JNK (c-Jun N-terminal kinase)-dependent mouse hepatocyte lipotoxicity induced by palmitate. IL-22 prevented lipotoxicity through PI3K (phosphoinositide 3-kinase)-mediated inhibition of JNK, but did not play a protective role in the presence of IL-17, which up-regulated the PI3K/Akt inhibitor PTEN (phosphatase and tensin homologue deleted on chromosome 10). Consistently, livers of IL-17(-/-) mice fed on the MCD diet displayed decreased activation of JNK, reduced expression of PTEN and increased phosphorylation of Akt compared with livers of wild-type mice. Hepatic infiltration of Th17 cells is critical for NASH initiation and development of fibrosis in mice, and reflects an infiltration of Th22 cells. Th22 cells are protective in NASH, but only in the absence of IL-17. These data strongly support the potentiality of clinical applications of IL-17 inhibitors that can prevent NASH by both abolishing the lipotoxic action of IL-17 and allowing IL-22-mediated protection.
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Department of Molecular Biotechnology and Health Sciences, via Nizza 56, University of Torino, 10126 Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rolla
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Alchera
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Imarisio
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Department of Molecular Biotechnology and Health Sciences, via Nizza 56, University of Torino, 10126 Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bardina
authors.affiliation: Department of Translational Medicine, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Valente
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Department of Molecular Biotechnology and Health Sciences, via Nizza 56, University of Torino, 10126 Turin, Italy Molecular Biology Center, University of Turin, via Nizza 52, 10126 Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.affiliation: Department of Translational Medicine, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mombello
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Department of Molecular Biotechnology and Health Sciences, via Nizza 56, University of Torino, 10126 Turin, Italy Immunogenetics and Transplantation Biology Unit, Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Molecular Biology Center, University of Turin, via Nizza 52, 10126 Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy rita.carini@med.uniupo.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Carini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000172:deficiency; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D000097043:Interleukin-22
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22
keywords: hepatocyte; immune reactions; lipotoxicity; phosphoinositide 3-kinase signalling; steatosis