Role of IL-17 and Th17 cells in liver diseases

Abstract

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4(+) T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease.

Figure 1

Differentiation of CD4⁺ T-cell subsets (in mice). Upon activation, naïve CD4⁺ T cells can differentiate into different subsets depending on the surrounding cytokine milieu. The different subpopulations show distinct expression patterns of transcription factors and can be characterized by secretion of signature cytokines that are unique for each subset. Each subset takes part in different kinds of immune responses against various pathogens or in mediating autoimmunity.

Figure 2

T-cell-mediated inflammation of the liver. Four different types of T-helper cell responses have been described to influence various inflammatory processes in the liver. Th1 responses lead to classical activation (M1) of liver-resident macrophages such as Kupffer cells as well as recruitment of monocytes from the bloodstream, promoting a proinflammatory environment by secretion of IFNγ, TNFα, and IL-12. Th1 infiltration is mediated mainly by engagement of chemokine receptors CXCR3 and CCR5. Th2-type responses are thought to lead to an alternative activation of macrophages (M2) via IL-4 and IL-13, leading to a profibrotic response by activation of hepatic stellate cells (HSC) and inducing their differentiation into myofibroblasts. Th2-type responses are linked mainly to CCR3- and CCR4- mediated chemokine signalling as well as potentially CCR8 under certain conditions. Th17 cell responses in the liver have only recently been described to be involved in various inflammatory processes induced, for example, by alcohol-induced liver disease, HCC, or HBV/HCV-induced hepatitis. Th17 cells lead to activation of macrophages and recruitment of neutrophils, inducing an innate response by secretion of cytokines such as IL-1β, IL-6, and TNFα but also regulatory factors such as TGFβ. Recruitment of Th17 cells may be associated with CCR6- and possibly also CCR4-mediated signalling. T regulatory cells (Treg) have been described to be mainly immunosuppressive, secreting anti-inflammatory cytokines such as IL-10 and TGFβ as well as consuming IL-2, which is a key factor for immunogenic activation of T cells. Therefore, Treg inhibit and suppress T-cell activation and effector functions as well as preventing activation of innate immune cells. A broad variety of chemokine receptors have been linked to Treg migration, for example, CCR1 and CCR4 but also CCR5 as well as CCR6, suggesting a functional overlap for these receptors in different T-helper cell responses.