The Multifaceted Roles of Macrophages in NAFLD Pathogenesis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome. NAFLD constitutes a spectrum of pathologies ranging from simple hepatic steatosis (nonalcoholic fatty liver) to the more progressive form of steatohepatitis and fibrosis, which can culminate in liver cirrhosis and hepatocellular carcinoma. Macrophages play multiple roles in the context of NAFLD pathogenesis by regulating inflammatory responses and metabolic homeostasis in the liver and thereby may represent an attractive therapeutic target. Advances in high-resolution methods have highlighted the extraordinary heterogeneity and plasticity of hepatic macrophage populations and activation states thereof. Harmful/disease-promoting as well as beneficial/restorative macrophage phenotypes co-exist and are dynamically regulated, thus this complexity must be taken into consideration in strategies concerning therapeutic targeting. Macrophage heterogeneity in NAFLD includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow–/monocyte-derived macrophages) as well as their functional phenotype, for example, inflammatory phagocytes, lipid- and scar-associated macrophages, or restorative macrophages. Here, we discuss the multifaceted role of macrophages in the pathogenesis of NAFLD in steatosis, steatohepatitis, and transition to fibrosis and hepatocellular carcinoma, focusing on both their beneficial and maladaptive functions at different disease stages. We also highlight the systemic aspect of metabolic dysregulation and illustrate the contribution of macrophages in the reciprocal crosstalk between organs and compartments (eg, the gut–liver axis, adipose tissue, and cardiohepatic metabolic interactions). Furthermore, we discuss the current state of development of pharmacologic treatment options targeting macrophage biology. Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome. NAFLD constitutes a spectrum of pathologies ranging from simple hepatic steatosis (nonalcoholic fatty liver) to the more progressive form of steatohepatitis and fibrosis, which can culminate in liver cirrhosis and hepatocellular carcinoma. Macrophages play multiple roles in the context of NAFLD pathogenesis by regulating inflammatory responses and metabolic homeostasis in the liver and thereby may represent an attractive therapeutic target. Advances in high-resolution methods have highlighted the extraordinary heterogeneity and plasticity of hepatic macrophage populations and activation states thereof. Harmful/disease-promoting as well as beneficial/restorative macrophage phenotypes co-exist and are dynamically regulated, thus this complexity must be taken into consideration in strategies concerning therapeutic targeting. Macrophage heterogeneity in NAFLD includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow–/monocyte-derived macrophages) as well as their functional phenotype, for example, inflammatory phagocytes, lipid- and scar-associated macrophages, or restorative macrophages. Here, we discuss the multifaceted role of macrophages in the pathogenesis of NAFLD in steatosis, steatohepatitis, and transition to fibrosis and hepatocellular carcinoma, focusing on both their beneficial and maladaptive functions at different disease stages. We also highlight the systemic aspect of metabolic dysregulation and illustrate the contribution of macrophages in the reciprocal crosstalk between organs and compartments (eg, the gut–liver axis, adipose tissue, and cardiohepatic metabolic interactions). Furthermore, we discuss the current state of development of pharmacologic treatment options targeting macrophage biology. SummaryDistinct macrophage populations are key drivers in promoting but also in attenuating disease progression during all states of nonalcoholic fatty liver disease pathogenesis, making them an attractive therapeutic target. This review provides an overview of the broad spectrum of functionally diverse macrophage phenotypes in nonalcoholic fatty liver disease and related systemic metabolic diseases. The focus was placed on pathogenic relationships and mechanistic interactions of different macrophage populations, as well as on possible therapeutic approaches targeting their (mal)function. Distinct macrophage populations are key drivers in promoting but also in attenuating disease progression during all states of nonalcoholic fatty liver disease pathogenesis, making them an attractive therapeutic target. This review provides an overview of the broad spectrum of functionally diverse macrophage phenotypes in nonalcoholic fatty liver disease and related systemic metabolic diseases. The focus was placed on pathogenic relationships and mechanistic interactions of different macrophage populations, as well as on possible therapeutic approaches targeting their (mal)function. Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the world, with a prevalence of 25% to 30% in Western societies.1Friedman S.L. Neuschwander-Tetri B.A. Rinella M. Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies.Nat Med. 2018; 24: 908-922Crossref PubMed Scopus (1634) Google Scholar NAFLD can progress to diseases associated with poor outcome, such as liver cirrhosis and hepatocellular carcinoma, placing an increasing burden on health care systems.1Friedman S.L. Neuschwander-Tetri B.A. Rinella M. Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies.Nat Med. 2018; 24: 908-922Crossref PubMed Scopus (1634) Google Scholar NAFLD is considered the hepatic manifestation of the metabolic syndrome because it is strongly associated with obesity, type 2 diabetes, dyslipidemia, and cardiovascular disease.2Kasper P. Martin A. Lang S. et al.NAFLD and cardiovascular diseases: a clinical review.Clin Res Cardiol. 2021; 110: 921-937Crossref PubMed Scopus (159) Google Scholar The collective term NAFLD encompasses various phenotypes of metabolic liver disease, ranging from simple fat accumulation termed hepatic steatosis or nonalcoholic fatty liver, to nonalcoholic steatohepatitis (NASH), displaying additional lobular inflammation and hepatocellular damage. In NASH, a proinflammatory hepatic microenvironment stimulates fibrogenic processes leading to liver fibrosis and, eventually, cirrhosis.3Engelmann C. Tacke F. The potential role of cellular senescence in non-alcoholic fatty liver disease.Int J Mol Sci. 2022; 23: 652Crossref PubMed Scopus (11) Google Scholar The only curative therapy for end-stage liver disease and the early stages of hepatocellular carcinoma is liver transplantation. Because of the increasing prevalence and lack of diagnostic and therapeutic strategies, NAFLD is likely to become the leading indication for liver transplantation in the near future.4Pais R. Barritt A.S. Calmus Y. et al.NAFLD and liver transplantation: current burden and expected challenges.J Hepatol. 2016; 65: 1245-1257Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar The pathogenic processes of NAFLD are incompletely understood. Within the liver, the disruption of the finely regulated interplay between hepatocytes, hepatic stellate cells, endothelial cells, and various immune cell subtypes, driven by secreted cytokines and mediators, can result in a proinflammatory, profibrotic, and protumorigenic hepatic microenvironment.5Peiseler M. Schwabe R. Hampe J. et al.Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.J Hepatol. 2022; 77: 1136-1160Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition, extrahepatic factors such as nutritional intake, gut dysbiosis, and systemic inflammation, as well as genetic disposition influence the disease processes in the liver.5Peiseler M. Schwabe R. Hampe J. et al.Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.J Hepatol. 2022; 77: 1136-1160Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Macrophages are innate immune cells that are abundant as resident cells in almost all organs of the body.6Krenkel O. Tacke F. macrophages in homeostasis and PubMed Scopus Google Scholar key functions in development and homeostasis but also may to pathogenesis of various diseases. the high-resolution such as and have of macrophage and Tacke F. Schwabe the cellular of non-alcoholic fatty liver 2022; Google Scholar also have as the complexity of macrophage and functional in different have highlighted the of and resident macrophage populations in almost all to as Kupffer cells in the In to resident phagocytes, the liver also bone and macrophages F. P. et to and Kupffer 2016; A. Tacke F. and PubMed Google M. The role of innate immune cells in nonalcoholic fatty liver 2022; PubMed Scopus Google Scholar resident macrophages functions regulated by the microenvironment in which M. A. S. and functional heterogeneity of 2018; Full Text Full Text PDF PubMed Scopus Google M. J. et distinct and hepatic macrophage 2022; Full Text Full Text PDF PubMed Scopus Google Scholar in the context of disease, the of a proinflammatory and a restorative state by a more that into the and plasticity of et activation and and Full Text Full Text PDF PubMed Scopus Google Scholar of the complexity of proinflammatory and restorative macrophage phenotypes in the et cell of liver distinct macrophage 2018; PubMed Scopus Google Scholar their in it is that macrophages play a diverse role in various O. Tacke F. macrophages in homeostasis and PubMed Scopus Google A. Tacke F. and PubMed Google Scholar the development of progression to NASH, fibrosis, and end-stage liver disease, as well as in the of associated such as hepatocellular carcinoma. In the in inflammatory macrophage populations and their distinct accumulation in and to are a key of progressive chronic liver but also or The of macrophage populations in both and inflammation, as well as their in and systemic metabolic them an attractive but therapeutic target. In this we the contribution of macrophages to different stages of metabolic liver disease and an on and potential therapeutic steatosis is by an accumulation of in more of S. S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease PubMed Scopus Google Scholar to be a between simple steatosis and the for the transition to the inflammatory of with steatosis steatohepatitis more with a steatosis S. S. 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