Plasticity of monocytes and macrophages in cirrhosis of the liver

Abstract

Cirrhosis of the liver is a systemic condition with raising prevalence worldwide. Patients with cirrhosis are highly susceptible to develop bacterial infections leading to acute decompensation and acute-on-chronic liver failure both associated with a high morbidity and mortality and sparse therapeutic options other than transplantation. Mononuclear phagocytes play a central role in innate immune responses and represent a first line of defence against pathogens. Their function includes phagocytosis, killing of bacteria, antigen presentation, cytokine production as well as recruitment and activation of immune effector cells. Liver injury and development of cirrhosis induces activation of liver resident Kupffer cells and recruitment of monocytes to the liver. Damage- and pathogen-associated molecular patterns promote systemic inflammation which involves multiple compartments besides the liver, such as the circulation, gut, peritoneal cavity and others. The function of circulating monocytes and tissue macrophages is severely impaired and worsens along with cirrhosis progression. The underlying mechanisms are complex and incompletely understood. Recent 'omics' technologies help to transform our understanding of cellular diversity and function in health and disease. In this review we point out the current state of knowledge on phenotypical and functional changes of monocytes and macrophages during cirrhosis evolution in different compartments and their role in disease progression. We also discuss the value of potential prognostic markers for cirrhosis-associated immuneparesis, and future immunotherapeutic strategies that may reduce the need for transplantation and death.

Keywords: ACLF; cirrhosis; immuneparesis; immunotherapy; inflammation; liver injury; macrophages; monocytes.

FIGURE 1

Definitions of decompensation and clinical stage of cirrhosis. Cirrhosis can be categorized in an asymptomatic compensated stage and decompensated stages with the onset of various complications. Decompensation can be characterised by progressive non-acute onset (non-acute decompensation, NAD) or acute onset (acute decompensation, AD). Progressive onset is defined as slow formation of ascites, low grade encephalopathy or progressive jaundice and doesn’t necessarily require hospitalization. AD is defined as rapid ascites formation within less than 2 weeks, acute hepatic encephalopathy, gastrointestinal bleeding or bacterial infection and usually requires hospitalization. AD presents as SDC with stable decrease of systemic inflammation and no further AD for at least 1 year, UDC characterised by persistent albeit unstable inflammatory status resulting in further AD events within 1 year, pre-ACLF with ACLF occurring within 3 months and ACLF defined by development of organ failure. During progression of cirrhosis mortality, fibrosis, portal hypertension and its associated clinical manifestations, the risk for episodes of infection increases and relates to the development of immune paresis. Adapted from (D’Amico et al., Journal of Hepatology 2022 and Bernsmeier et al., Journal of Hepatology 2020). ACLF, acute-on-chronic liver failure; SDC, stable decompensated cirrhosis; UDC, unstable decompensated cirrhosis.

FIGURE 2

Current knowledge on monocyte and macrophage plasticity in relation to the multi-compartmental pathophysiological mechanisms underlying cirrhosis progression and decompensation. The main pathophysiological mechanisms underlying cirrhosis progression and acute decompensation are shown. These include liver fibrosis, hepatic endothelial dysfunction, parenchymal damage, portal hypertension, dysbiosis, bacterial translocation as well as activation of both local and systemic inflammatory responses. A variety of cellular and non-cellular players involved in these mechanisms are depicted (see symbol legend). In summary, homeostatic monocyte and macrophage populations display a distinct phenotype and function in a compartment-specific manner. Changes in monocyte/macrophage differentiation and migration patterns with progression of cirrhosis and acute decompensation are due to multiple factors involving chronic inflammation, exposure to DAMPs (released by injured hepatocytes) as well as exposure to PAMPs/microbial products due to dysbiosis and pathological bacterial translocation. Distinct cell subsets are shown in gut, liver, circulation and peritoneum, underlining the multi-compartmental nature of the disease. Adapted from Bernsmeier et al., Journal of hepatology 2020. ACLF, acute-on-chronic liver failure; LPM, large peritoneal macrophage; SPM, small peritoneal macrophage; M-MDSC, monocytic myeloid-derived suppressor cell; SAM, scar-associated macrophage; MDM, monocyte-derived macrophage; HSC, hepatic stellate cell; PHT, portal hypertension; GALT, gut-associated lymphoid tissue; DAMP; damage-associated molecular patterns; PAMP, pathogen-associated molecular pattern. Created with BioRender.com.