Inflammatory responses on the road from NASH to HCC: pathogenic mechanisms and possible therapeutic strategies

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(A) Enrichment of CD56+ NK cells by magnetic-activated cell sorting (MACS) as quantified by flow cytometry (FACS). Normalized enrichment after MACS purification against the other cell type proportions before enrichment. (B) FACS plots of NK cell activation markers. The cell surface markers CD69 and NKp30 were stained and measured in NK cells stimulated with phorbol 12-myristate 13-acetate (PMA) or IL-2+IL-15. (C) Relative mRNA expression of NK cell activation markers. NK cells were stimulated for 6 h and used for the qPCR quantification of IL-1β, CD69, and NKp30. (D) CD56+ NK cells secreted IL-6, IL-8, TNF-α, TGF-β1, Granzyme A, and IFN-Υ as quantified by MSD-ELISA. One-way ANOVA with Benjamini–Krieger correction; *p < 0.05, **p < 0.01, ****p < 0.0001.

Chronic liver diseases, such as non-alcoholic steatohepatitis (NASH)-induced cirrhosis, are characterized by an increasing accumulation of stressed, damaged, or dying hepatocytes. Hepatocyte damage triggers the activation of resident immune cells, such as Kupffer cells (KC), as well as the recruitment of immune cells from the circulation toward areas of inflammation. After infiltration, monocytes differentiate into monocyte-derived macrophages (MoMF) which are functionally distinct from resident KC. We herein aim to compare the in vitro signatures of polarized macrophages and activated hepatic stellate cells (HSC) with ex vivo-derived disease signatures from human NASH. Furthermore, to shed more light on HSC activation and liver fibrosis progression, we investigate the effects of the secretome from primary human monocytes, macrophages, and NK cells on HSC activation. Interleukin (IL)-4 and IL-13 treatment induced transforming growth factor beta 1 (TGF-β1) secretion by macrophages. However, the supernatant transfer did not induce HSC activation. Interestingly, PMA-activated macrophages showed strong induction of the fibrosis response genes COL10A1 and CTGF, while the supernatant of IL-4/IL-13-treated monocytes induced the upregulation of COL3A1 in HSC. The supernatant of PMA-activated NK cells had the strongest effect on COL10A1 induction in HSC, while IL-15-stimulated NK cells reduced the expression of COL1A1 and CTGF. These data indicate that other factors, aside from the well-known cytokines and chemokines, might potentially be stronger contributors to the activation of HSCs and induction of a fibrotic response, indicating a more diverse and complex role of monocytes, macrophages, and NK cells in liver fibrosis progression.

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Review
17 January 2024
From MASH to HCC: the role of Gas6/TAM receptors
Daria Apostolo
, 8 more and 
Mattia Bellan

Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.

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6 citations
Wild type (WT) and ICOSL deficient (ICOSL ko) mice were fed with either control or Western (WD) diets for 24 weeks and investigated for NAM/SAM markers. (A) hepatic mRNA levels of TREM2, Galectin-3 (Gal-3) and Osteopontin (OPN). RT-PCR values are expressed as fold increase of 2-ΔCT over the relative control samples. The values in the panel refer to 5-8 animals per group and the boxes include the values within 25th and 75th percentile, while the horizontal bars represent the median. The extremities of the vertical bars (10th-90th percentile) include 80% of the values. (B) Immunohistochemical detection of Gal-3 and OPN (arrows) in liver sections (magnification 20x). Quantification was performed by counting, respectively, Gal-3 positive hepatic crown-like structures (hCLS) or OPN positive cells in 10 microscopic fields at 20x magnification.

Background and aims: Inducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associated steatohepatitis (MASH).

Results: In animal models of MASH, ICOS was selectively up-regulated on CD8+ T-cells in parallel with an expansion of ICOSL-expressing macrophages. An increase in circulating soluble ICOSL was also evident in patients with MASH as compared to healthy individuals. ICOSL knockout (ICOSL-/-) mice receiving choline/methionine deficient (MCD) diet for 6 weeks had milder steatohepatitis than wild type mice. MASH improvement was confirmed in mice fed with cholesterol-enriched Western diet for 24 weeks in which ICOSL deficiency greatly reduced liver fibrosis along with the formation of crown-like macrophage aggregates producing the pro-fibrogenic mediators osteopontin (OPN) and galectin-3 (Gal-3). These effects associated with a selective shewing of F4-80+/CD11bhigh monocyte-derived macrophages (MoMFs) expressing the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to CD11blow/F4-80+ cells positive for the Kupffer cell marker C-type lectin-like type 2 receptor (CLEC-2), thus indicating an increased MoMF maturation toward monocyte-derived Kupffer cells.

Conclusions: These results suggest that CD8+ T-cells interaction with monocyte-derived macrophages through ICOS/ICOSL critically supports a specific subset of TREM2+-expressing cells contributing to the evolution of steatohepatitis. The data also point ICOS/ICOSL dyad as a possible target for therapeutic interventions in MASH.

3,558 views
4 citations