Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

Keywords: cancer immunotherapy; hepatocellular carcinoma; inflammation; innate immunity; macrophages; nonalcoholic steatohepatitis.

Figure 1

The fate of monocytes and macrophages in steatohepatitis. In homeostasis (left panel), the liver is populated with embryonic Kupffer cells (EmKC) that are maintained by self-renewal and have, in principle, a tolerogenic phenotype. Specific markers for Kupffer cells in mice are Tim4, Clec4F and Clec2. In steatohepatitis (right panel), lipid-induced stress impairs embryonic Kupffer cell replication, inducing cell death and resulting in their gradual loss. Infiltrating monocytes have at least two distinct fates: as monocyte-derived KC (MoKC) with largely overlapping gene signatures albeit more proinflammatory. They occupy the Kupffer cell niche and replenish EmKC. Alternatively, monocytes give rise to lipid-associated macrophages (LAM) or scar-associated macrophages (SAM) with the expression of CD9, TREM2 and osteopontin, show differences in lipid and inflammatory genes and a location in proximity to the fibrotic niche.

Figure 2

Multiple systems drive inflammation and progression of nonalcoholic fatty liver disease (NAFLD). An interorgan crosstalk between adipose tissue, intestine, bone marrow, and liver triggers the inflammatory cascade in steatohepatitis. In adipose tissue (top right), excess lipids lead to hypertrophy and induce the release of proinflammatory mediators such as IL-1β, IL-6, TNF, and CCL2 and influx of inflammatory cells. Furthermore, disturbed adipokines (low adiponectin and high leptin) and increased free fatty acids (FFA) induce lipotoxic effects in the liver. In bone marrow (bottom right), inflammatory mediators increase myelopoiesis and decrease lymphopoiesis. In the gut (bottom left), disrupted intestinal barrier leads to increased levels of pathogen-associated molecular patterns (PAMPs), such as LPS that enter the circulation and portal vein, stimulating inflammation in liver and myelopoiesis in the bone marrow. Increased systemic inflammation, hepatocyte death and endotoxins in concert drive liver inflammation. In a vicious cycle, the liver produces more inflammatory mediators such as acute-phase proteins and complement, further corroborating inflammation. Bile acids from the liver modify the intestinal microbiota and regulate inflammatory/regulatory cells, including T cells.