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.

Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights

“…In this study, WT mice were fed an MCD diet for 8 weeks, subsequently developed NASH with fibrosis, and were shown to have increased infiltration of T helper 17 (Th17) and T helper 22 (Th22) cells, which play a role in inflammation 29 . Infiltration of Th17 cells increased at both the beginning of the development of NASH and at the transition to NASH with fibrosis, and there was increased infiltration of Th22 cells between these two phases 29 . Considering that NAFL (which presents with little to no fibrosis) can progress to NASH with significant fibrosis 30 , this association between inflammation, inflammatory cell infiltration and hepatic fibrosis development gives important insight into the pathophysiology of these diseases.…”

“…In a study by Rolla et al the authors examined the role of hepatic inflammation in the development of NASH with fibrosis in the MCD diet mouse model 29 . In this study, WT mice were fed an MCD diet for 8 weeks, subsequently developed NASH with fibrosis, and were shown to have increased infiltration of T helper 17 (Th17) and T helper 22 (Th22) cells, which play a role in inflammation 29 .…”

“…In a study by Rolla et al the authors examined the role of hepatic inflammation in the development of NASH with fibrosis in the MCD diet mouse model 29 . In this study, WT mice were fed an MCD diet for 8 weeks, subsequently developed NASH with fibrosis, and were shown to have increased infiltration of T helper 17 (Th17) and T helper 22 (Th22) cells, which play a role in inflammation 29 . Infiltration of Th17 cells increased at both the beginning of the development of NASH and at the transition to NASH with fibrosis, and there was increased infiltration of Th22 cells between these two phases 29 .…”

“…Since fibrosis is the precursor lesion of cirrhosis, it is important to understand the mechanisms underlying the development of fibrosis in NAFLD. Several studies have shown that an MCD diet can eventually induce hepatic fibrosis in WT mice 23,24,29,31,34–39 ; however, the time required for mice to develop fibrosis while on an MCD diet varies. In studies by Katsura et al and Simon et al, mice fed an MCD diet for 15 weeks or 2 weeks, respectively, developed fibrosis 35,38 .…”

Serum Concentrations of Th17-Associated Interleukins and Autoimmune Phenomena are Associated with the Degree of Liver Damage in Alcoholic Liver Disease

“…Numerous researches provided evidence for the hepatoprotective role of IL-22 in liver damage [17,18]. In animal models of non-alcoholic steatohepatitis (NASH) IL-22 alone exerted hepatoprotective activity, but this effect was lost in the presence of IL-17 [19]. On the other hand, the study of Wu et al has shown that IL-22 alone was involved in the stimulation of hepatic fibrogenesis [20].…”