Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting

Abstract

Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

“…Interestingly, a distinct population of scar-associated macrophages deriving from recruitment and differentiation of circulating monocytes has been identified, following liver damage. This macrophage subtype has an important role in resolution of liver fibrosis, representing one of the sources of MMP13 in fibrotic niches in livers of cirrhotic patients [132]. During the early stages of liver injury, scar-associated macrophages differentiate into inflammatory macrophages, and subsequently switch to an anti-inflammatory phenotype, which secretes a wide variety of MMPs to facilitate fibrosis resolution [133,134].…”

The Gut–Liver Axis in Chronic Liver Disease: A Macrophage Perspective

“…Indeed, in NAFLD patients, LPS-induced activation of liver MFs is associated with inflammation and fibrosis, and both TLR4 knockout (KO) and clodronate-mediated hepatic MF depletion attenuate experimental NASH [ 132 , 133 ]. Preventing hepatic MF activation by targeting the LPS–TLR4 axis may thus represent a valid therapeutic strategy for CLD, especially since pharmacological inhibition of TLR4 has already been shown to ameliorate liver injury and inflammation in experimental fibrosis/cirrhosis [ 130 , 134 ]. In addition to LPS, other gut-derived bacterial metabolites are involved in hepatic MF-mediated immunity as well [ 130 ].…”

“…Chronic ethanol administration in mice leads to an altered intestinal mycobiome, with increased translocation of β-glucan to the liver, leading to hepatic MF-induced liver injury and inflammation [ 136 ]. An effective strategy to prevent MAMP-mediated MF activation in CLD might be restoration of eubiosis using broad-spectrum antibiotics, probiotics, and fecal microbiota transfer [ 11 , 134 ]. In mice receiving HFD, modulation of the gut microbiome through the administration of inulin was found to reduce TLR4-mediated hepatic MF activation and prevent NAFLD development [ 137 , 138 ].…”

“…In the liver, in addition to exposure to persistent hepatic injury-associated DAMPs, increased intestinal translocation of harmful MAMPs can activate resident KCs through pattern recognition receptors [ 134 , 175 , 317 , 319 ], resulting in CXCL1-, CXCL2- and CXCL8-dependent recruitment of neutrophils, as well as the recruitment of Ly6C hi monocytes, mediated by several CCLs, including CCL2, CCL3, and CCL5 [ 12 , 126 , 322 , 323 ]. The crucial role of monocyte recruitment in fibrogenesis has been emphasized by several studies in which pharmacological inhibition or genetic deletion of certain CCLs/CCRs in experimental mouse models of fibrosis resulted in attenuation of disease [ 139 , 324 , 325 ].…”

“…In this view, despite the feasibility of ex vivo differentiation of cirrhotic patients’ CD14 + monocytes into pro-resolution MFs, pharmacological modulation of MF recruitment or polarization seems to be a more straightforward option [ 10 , 323 , 343 ]. A broad range of hepatic MF-targeting strategies have shown therapeutic potential in experimental animal models of liver fibrosis, but only a handful of them have already advanced to clinical trials [ 11 , 134 , 140 ]. Further efforts to improve our understanding of MF heterogeneity, plasticity, and function during liver fibrosis in order to promote the identification of novel, promising treatment options are thus of need.…”