The Role of Innate Lymphoid Cells in Immune-Mediated Liver Diseases

Abstract

Innate lymphoid cells (ILCs) are a recently identified group of innate immune cells lacking antigen-specific receptors that can mediate immune responses and regulate tissue homeostasis and inflammation. ILCs comprise group 1 ILCs, group 2 ILCs, and group 3 ILCs. These ILCs usually localize at mucosal surfaces and combat pathogens by the rapid release of certain cytokines. However, the uncontrolled activation of ILCs can also lead to damaging inflammation, especially in the gut, lung, and skin. Although the physiological and pathogenic roles of ILCs in liver diseases have been attracting increasing attention recently, there has been no systematic review regarding the roles of ILCs in immune-mediated liver diseases. Here, we review the relationships between the ILC subsets and their functions in immune-mediated liver diseases, and discuss their therapeutic potential based on current knowledge about the functional roles of these cells in liver diseases.

Keywords: conventional NK; immune-mediated disease; innate lymphoid cells; liver; liver disease; liver-resident NK.

Figure 1

The development and functions of innate lymphoid cell (ILC) subsets and their associated adaptive lymphocyte subsets. All ILCs arise from an early innate lymphoid precursor (EILP), which is generated from the common lymphoid progenitor (CLP). ILC1s, ILC2s, and ILC3s differentiate from a common helper-like innate lymphoid precursor (CHILP) arising from EILP. Conventional NK cells (cNK) differentiate from NK cell progenitors (NKPs) arising from EILPs. Lymphoid tissue inducer (LTi) cells are a subset of innate lymphocytes that interact with stromal cells to facilitate the development of lymphoid organs. The cytokines secreted by ILCs and helper T cells promote type 1, 2, and 3 immune responses. Group 1 ILCs contain cNK and ILC1s; group 2 ILCs is the all-inclusive term for ILC2s; group 3 ILCs comprise NCR⁺ILC3s, NCR⁻ILC3s, and LTis. Unlike other helper-like ILCs, ILC1s are dependent on IL-15 signaling and not on IL-7. AHR, aryl hydrocarbon receptor; E4BP4, E4 promoter-binding protein 4 (also known as NFIL3); GATA3, GATA-binding protein 3; ID2, inhibitor of DNA binding 2; NCR, natural cytotoxicity receptor; NKP, NK cell precursor; ROR, retinoic acid receptor-related orphan receptor; Th, T helper.

Figure 2

The protective or pathogenic roles of innate lymphoid cells (ILCs) in liver diseases. The hepatic ILC subsets are involved in the immune regulation of liver diseases (viral hepatitis, mechanical liver injury, and fibrosis). ① In hepatic adenovirus (Ad) or HCV infection, hepatic ILC1s play an important role in maintaining liver tolerance. Hepatic viral infection increases NKG2A expression on ILC1s, and NKG2A signaling in ILC1s inhibits CXCL9 expression, which is required for the accumulation of IFN-γ⁺CD49b⁺ NK cells (cNK cells). This, in turn, results in the loss of IFN-γ production, which is crucial for the enhanced priming of CD8⁺ T cells. ② Hepatic ILC1s and cNKs contribute to liver regeneration. cNK cells and ILC1s produce a high level of IL-22 in response to elevated adenosine triphosphate (ATP) and IL-23 in an ATP receptor P2X1 (P2-type nucleotide receptors)-dependent manner; IL-22 promotes hepatocyte growth via activation of the STAT3 pathway. ③ Hepatic cNK or ILC1s limit liver fibrosis. The inflammatory cytokine TNFα increases expression of TNF-related apoptosis-inducing ligand (TRAIL) on cNK cells, and then enhances cNK cell-mediated hepatic stellate cell (HSC) killing. The high expression of TRAIL may lead to hepatic ILC1s having similar effects to the killing of activated HSC, thus limiting liver fibrosis. ④ In Ad-induced liver inflammation, ILC2s exhibit a hepatoprotective role. The expression of IL-33 and its receptor ST2 in the liver are increased, and the ILC2s expand in response to IL-33 and limit liver injury by suppressing TNFα production in hepatic T cells and macrophages. ⑤ In Con A-induced hepatitis, hepatic ILC2s are activated and expanded in response to IL-33, further amplifying inflammatory immune responses via IL-5-mediated recruitment of eosinophils. The inflammatory activity of ILC2s might be regulated by IL-33-expanded CD4⁺Foxp3⁺ regulatory T cells (Treg). ⑥ In CCl₄-or thioacetamide (TAA)-induced chronic hepatocellular stress, IL-33 activates ILC2s, producing IL-13, leading to HSC activation through IL-13Rα1- and STAT6-dependent signaling. ⑦ Hepatitis B virus infection induces IL-23 production by antigen-presenting cells, and the increased IL-23 contribute to liver damage via IL-17 production, possibly by activating the IL-23 receptor-expressing ILC3s. ⑧ In CCl₄-induced acute hepatitis, the IL-22-producing ILC3s inhibit liver injury via IL-22 production. ⑨ In the pathogenesis of hepatic ischemia reperfusion injury (IRI), RORγt-expressing NKp46⁺ cells are capable of ameliorating hepatic IRI in an IL-22-dependent manner.