Regulation of Monocyte-Macrophage Responses in Cirrhosis-Role of Innate Immune Programming and Checkpoint Receptors

Abstract

Many aspects of the innate immune system have been studied in cirrhosis, and abnormalities have been described supporting both a pro-inflammatory and anti-inflammatory phenotype of myeloid cells. However, the findings of these studies vary by stage of disease and methodology. The recent description of the syndrome of acute-on-chronic liver failure (ACLF) has refined our understanding of the natural history of cirrhosis. In this context, we review the regulatory mechanisms at play that contribute to the immune abnormalities described in advanced liver disease. Specifically, we review the evidence for epigenetic mechanisms regulating monocyte phenotype, and the role of checkpoint receptors on regulating innate and adaptive immune cell function.

Keywords: ACLF; ALD; ARLD; alcoholic hepatitis; cirrhosis; immune checkpoint; innate immune cell; myeloid.

Figure 1

Immunological phenomena associated with progression of cirrhosis. Increasing disease severity is accompanied by the establishment of a skewed immune profile, characterized by concurrent systemic inflammation and deficient immune protection. This state of cirrhosis-associated immune dysfunction (CAID) is crucial in increasing the risk of life-threatening microbial infection, and is in part mediated by a dysregulation of the immune checkpoint network [reviewed in (9)].

Figure 2

Features of anti-inflammatory monocytes. During acute excessive inflammation monocytes can acquire an anti-inflammatory phenotype. Mechanisms behind this phenomenon are not fully understood, but chronic and intense stimulation with PAMPs and DAMPs, consequent to microbial infection or tissue damage/injury, seems able to facilitate it. PGE2 also seems to play a role in enabling monocyte changes. Anti-inflammatory monocytes appear tolerised to bacterial endotoxin, possibly linked to loss of CD14. High CD16 and MerTK have also been described. Monocyte expression of inhibitory immune checkpoints has been linked to a more suppressive phenotype, with preferential IL-10 production, and worse prognosis in cancer, infections and sepsis. Epigenetic reprogramming, and its effect on intracellular metabolic pathways, are also observed in anti-inflammatory monocytes.