Active role of the immune system in metabolic dysfunction-associated steatotic liver disease

Abstract

Non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a complex multifactorial disease that progresses from steatohepatitis (MASH) to liver cirrhosis and liver cancer. Recent research has revealed that crosstalk between innate immune cells and hepatic parenchymal and non-parenchymal cells is involved in the pathogenesis of liver disease in MASLD/MASH. Of particular importance, novel inflammatory mechanisms, including macrophage diversity, neutrophil NETosis, B-cell biology, auto-reactive T cells, unconventional T cells, and dendritic cell-T cell interactions, are considered key drivers for disease progression. These mechanisms and factors are potential targets for the therapeutic intervention of MASLD/MASH. In this review, we focus on recent discoveries related to liver inflammation and discuss the role of innate immune cell subsets in MASLD/MASH.

Keywords: MASH; MASLD; inflammatory cytokine; innate immunity; liver fibrosis.

Figure 1.

Recently reported mechanisms of the immune cell-mediated regulation of MASLD. This figure illustrates the involvement of immune cells in MASLD, based mainly on recent findings using mouse models. Bone-marrow-derived monocytes sense hepatocyte death signals and differentiate into restorative or inflammatory Mo/MF. Simultaneously, monocytes differentiate into LAMs or emerge as SAMs in fibrotic niches upon interaction with steatotic hepatocytes. Regarding KCs, the resident type KC1 is converted into KC2, a phenotype with high CD36 expression, due to impaired self-renewal by FFAs that are derived from steatotic hepatocytes. MoKCs with a KC-like phenotype also emerge from monocytes and replace the impaired KC1 population. While MP2 is responsible for immunosuppression by sensing bacteria via Marco in a steady state, it decreases in MASLD. Neutrophils accumulate early in MASLD and promote disease progression via cytokine production. NETosis induces HSCs activation and suppresses tumor immunity by inhibiting effector T cells through the induction of Tregs. Pre-DC precursors that increase in the bone marrow mature in the hepatic lymph nodes and differentiate into XCL1⁺ cDC1 in the liver. Activated effector memory CD8⁺ T cells by cDC1 are involved in the pathogenetic progression of MASLD. CD20A⁺IgA⁺ B cells that are induced in the small intestine form clusters with CD8⁺ T cells and induce the activation of CD8⁺ T cells. These B cells also induce Fcgr⁺S100a4⁺ Mo/MF in the liver via IgA production and are involved in the progression of MASLD. CD8⁺ T cells are converted into CXCR6⁺FasL⁺Foxo^low auto-aggressive T cells by acetate, a metabolic product of fatty hepatic cells, and contribute to the development of MASH. While innate-like T cells play a role in promoting fibrosis through the release of cytotoxic factors in MASH, they also contribute to the apoptosis of hepatic stellate cells (anti-fibrosis). MASLD = metabolic dysfunction-associated steatotic liver disease, Mo/MF = monocyte/macrophage, KCs = Kupffer cells, LAM= lipid-associated macrophages, SAMs = scar-associated macrophages, MoKCs = monocyte-derived Kupffer cells, MP2 = Marco⁺ Kupffer cell subset, FFAs = free fatty acids, NETosis = neutrophil extracellular traps-osis, MPO = myeloperoxidase, HSCs = hepatic stellate cells, Tregs = regulatory T cells, HCC = hepatocellular carcinoma, cDC = conventional dendritic cell, NK = natural killer, NKT = natural killer T, γδ T = gamma delta T.