Abstract
Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. This paradigm of tissue injury succeeded by immunosuppression is seen in other inflammatory conditions such as sepsis, which share poor outcomes and infective complications that account for high morbidity and mortality. Monocyte and macrophage dysfunction are central to disease progression of ALF and ACLF. Activation of liver-resident macrophages (Kupffer cells) by pathogen and damage associated molecular patterns leads to the recruitment of innate effector cells to the injured liver. Early monocyte infiltration may contribute to local tissue destruction during the propagation phase and results in secretion of pro-inflammatory cytokines that drive SIRS. In the hepatic microenvironment, recruited monocytes mature into macrophages following local reprogramming so as to promote resolution responses in a drive to maintain tissue integrity. Intra-hepatic events may affect circulating monocytes through spill over of soluble mediators and exposure to apoptotic cell debris during passage through the liver. Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for further research and potential targets for immune-based therapies to treat these devastating conditions.
Highlights
The liver is a unique innate immune environment and exerts crucial immune surveillance functions during homeostasis [1, 2]
The liver houses an abundant population of tissueresident macrophages, as intrasinusoidal Kupffer cells (KC), which function as the dominant phagocytes in the liver and compose over 80% of the body’s macrophages in states of health
prostaglandin E2 (PGE2) was shown to inhibit macrophage pro-inflammatory cytokines in response to LPS and decrease macrophage bacterial killing [115]. We have revealed another mechanism explaining immuneparesis in acute-on-chronic liver failure (ACLF), that involves the activation of MerTK on monocytes/macrophages in the circulation and tissue sites of inflammation in these patients [77]
Summary
The liver is a unique innate immune environment and exerts crucial immune surveillance functions during homeostasis [1, 2] It has a dual blood supply, it is constantly exposed to circulating antigens, pathogens, pathogen-associated toxins, and danger signals which reach the liver from the gastrointestinal tract, via the portal vein, or from the systemic circulation via arterial blood [3]. The liver houses an abundant population of tissueresident macrophages, as intrasinusoidal Kupffer cells (KC), which function as the dominant phagocytes in the liver and compose over 80% of the body’s macrophages in states of health It contains other myeloid [neutrophils and dendritic cells (DCs)] and lymphoid [T cells, natural killer (NK) cells, and NK T cells] cells that shape innate and adaptive immune responses [2, 4]. The exact definition of ACLF has been debated in the community, with the Asian Pacific Association for the Study of the Liver (APASL),
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