Abstract
Simple SummaryNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting a quarter of the global population and carries the risk of developing malignant liver cancer. Inflammation is considered paramount in the progression of the disease and many different immune cells and pathways have been implicated in the development of NAFLD. Novel techniques in basic immunology have substantially enhanced the possibilities to study inflammation and the heterogeneity of immune cells. Based on recent studies, we provide a review of novel paradigms emerging in steatohepatitis and the development of hepatocellular carcinoma and outline the multifaceted contributions of immunity to advancing NAFLD. End-stage NAFLD with liver cancer has an abysmal prognosis and effective medical therapies are lacking, therefore a better understanding of the disease mechanisms will ultimately help to improve patients’ care. 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting about 25% of the global population and is the fastest growing cause of hepatocellular carcinoma (HCC) [1]
NAFLD comprises a spectrum of chronic liver disease, ranging from isolated hepatic steatosis, to nonalcoholic steatohepatitis (NASH) characterized by steatosis, necroinflammation and hepatocyte injury with or without fibrosis, to cirrhosis and/or HCC [6,7]
Congruent with the aforementioned studies, loss of embryonic Kupffer cells and replacement with different subsets of monocyte-derived Kupffer cells and macrophages was found in steatohepatitis, including a population expressing CD9 and TREM-2, that localized in the fibrotic niche, corresponding to scar-associated macrophages found in humans [43,46]
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting about 25% of the global population and is the fastest growing cause of hepatocellular carcinoma (HCC) [1]. NAFLD comprises a spectrum of chronic liver disease, ranging from isolated hepatic steatosis, to nonalcoholic steatohepatitis (NASH) characterized by steatosis, necroinflammation and hepatocyte injury with or without fibrosis, to cirrhosis and/or HCC [6,7]. With NAFLD rising rapidly in recent years, NASH cirrhosis is a leading cause of liver transplantation [9]. The rising global prevalence of NAFLD and HCC represent major clinical challenges, further complicated by the lack of approved drugs for NAFLD and organ shortage for transplantation. In a complex multisystem disease, such as NAFLD, the immune system is constantly torn between inflammation, repair and tumor surveillance—in light of novel immunotherapies for HCC, an improved understanding of the precise immune pathways is necessary
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