The Role of Monocytes and Macrophages in Acute and Acute-on-Chronic Liver Failure

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.

Keywords: acute liver failure; acute-on-chronic liver failure; damage-associated molecular patterns; immunosuppression; liver inflammation; macrophages; monocytes; pathogen-associated molecular patterns.

Figure 1

Monocytes and macrophages in the immunopathology of acute and acute-on-chronic liver failure. (Left) Different causes lead to development of acute (bottom) and acute-on-chronic (top) liver failure. A major component of the immunopathology of both syndromes is liver inflammation initiated by release of various DAMPs and DAMPs/PAMPs, respectively. (Right) During these syndromes, there is a reciprocal interaction of the immune responses between the liver and systemic circulation throughout the different phases. Initiation phase: Kupffer cells become activated after recognition of PAMPs/DAMPs and initiate a pro-inflammatory response. Propagation phase: Bone-marrow derived monocytes are recruited to the liver and differentiate into inflammatory macrophages, expanding the macrophage pool and promoting tissue destruction. During the propagation phase, innate immune activation is self-perpetuating with recruitment of effector cells driving further cytokine and chemokine production; their release to systemic circulation provokes SIRS. These macrophage-derived mediators contribute to vascular endothelial dysfunction and microcirculatory disturbances, resulting in extra-hepatic organ dysfunction. In parallel to SIRS, a CARS develops that is due to release of anti-inflammatory mediators from the liver. Resolution/tissue-repair phase: In response to anti-inflammatory cytokines/mediators and efferocytosis of apoptotic cells, macrophages undergo functional reprogramming toward a pro-restorative phenotype, favoring resolution, and tissue recovery. “Spill over” of anti-inflammatory mediators from the liver to systemic circulation enhances CARS and causes monocyte functional reprogramming toward a pro-restorative phenotype, eventually leading to relative immunosuppression that predisposes susceptibility to infectious complications. CARS, compensatory anti-inflammatory response syndrome; CD, cluster of differentiation; DAMP, damage-associated molecular pattern; DILI, drug-induced liver injury; GI, gastrointestinal bleeding; HGF, hepatocyte growth factor; HLA-DR, human leukocyte antigen-DR; IL, interleukin; MerTK, Mer Tyrosine Kinase receptor; NASH, non-alcoholic steatohepatitis; PAMPs, pathogens-associated molecular patterns; PGE2, prostaglandin E2; ROS, reactive oxygen species; SIRS, systemic inflammatory response syndrome; SLPI, secretory leukocyte protease inhibitor; TNF-α, tumor necrosis factor-alpha.

Figure 2

Murine monocyte and liver macrophage subsets and targeted therapeutic strategies. (A) In mice, (left) blood and liver-infiltrating monocytes differentially express the markers Ly6C, CCR2, and CX3CR1. During steady-state, the liver macrophage pool can be expanded due to recruitment of circulating (CCR2⁺) Ly6C^high monocytes, a process markedly increased after injury. Following their infiltration, monocytes undergo a maturation process into (middle) (CX3CR1⁺) Ly6C_low monocyte-derived macrophages (MoMFs) that exhibit a CD11b^high F4/80⁺ profile. In contrast, the (right) embryonically derived (CX3CR1⁻) liver-resident Kupffer cells (KCs) are CD11b⁺ F4/80^high cells expressing the prototypical markers Clec4F and Tim4. Markers designated in bold are currently used to distinguish these two subsets. (B) The table summarizes therapeutic interventions targeting monocyte recruitment, macrophage polarization/differentiation or KC activation in experimental models of acute liver injury. CCL2, CC-chemokine ligand 2; CCR2, CC-chemokine receptor 2; CD, cluster of differentiation; Clec4F, C-type-lectin-domain-family-4-member-F; CSF1R, macrophage colony-stimulating-factor-1 receptor; CX3CR1, CX3C-chemokine receptor 1; DAMP, damage-associated molecular pattern; HMGB-1, high-mobility group box-1; IL, interleukin; MHCII, major histocompatibility complex class II; PRR, pattern-recognition receptor; PGE2, prostaglandin E2; SLPI, secretory leukocyte protease inhibitor; Tim-4, T-cell-immunoglobulin-and-mucin-domain-containing-4; TLR, Toll-like receptor.

Figure 3

Characteristics of human pro-restorative monocytes and macrophages in acute liver failure syndromes. The schematic summarizes the phenotypic and functional characteristics of (Left) steady-state inflammatory and (Right) pro-restorative monocytes and macrophages described in acute liver failure syndromes, which can arise in response to micro-environmental cues (IL-10, SLPI, PGE₂), CCR, CC-chemokine receptor; CD, cluster of differentiation; HGF, hepatocyte growth factor; HLA-DR, human leukocyte antigen-DR; IFN-γ, interferon gamma; IL, interleukin; MerTK, Mer Tyrosine Kinase receptor; NF-κB, nuclear factor-κB; PGE2, prostaglandin E2; SLPI, secretory leukocyte protease inhibitor; Tie2, angiopoietin receptor: TNF-α, tumor necrosis factor-alpha; TLR, Toll-like receptor.