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.
Highlights
Liver disease is a global health burden with recent estimates suggesting that 844 million people worldwide have chronic liver disease (CLD), with a mortality rate of 2 million deaths per year: approximately, 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma (HCC) [1, 2]
Most commonly caused by alcohol, infection or liver fat accumulation associated with features of the metabolic syndrome, triggers the activation of liver-resident and infiltrating immune cells, resulting in inflammation, progressive fibrosis, disrupted architecture, vascular changes and aberrant regeneration, which are defining characteristics of liver cirrhosis [2]
Intensive research over recent years has significantly improved our knowledge on macrophage diversity and plasticity in the context of liver diseases
Summary
Liver disease is a global health burden with recent estimates suggesting that 844 million people worldwide have chronic liver disease (CLD), with a mortality rate of 2 million deaths per year: approximately, 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma (HCC) [1, 2]. Circulating monocytes, a key component of the mononuclear phagocyte immune system, play pivotal roles in defence against infections and contribute to the systemic inflammation in chronic liver failure They augment the local macrophage pool via their recruitment to inflammatory sites after a sterile/tissue-damaging or infectious insult to the liver [10, 16, 25]. Brenig et al recently identified a distinct immune-regulatory population of (CD14+HLA-DR+) AXL-expressing monocytes that is expanded in parallel with progression of cirrhosis prior to the AD/ACLF stage and correlates with development of infection and one-year mortality [33] This subset displayed attenuated TNF-a and IL-6 secretion following TLR stimulation, reduced T cell activation but had preserved bacterial phagocytosis and enhanced efferocytosis capacity [33]. This needs further clinical evaluation [35]
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