The Biological Function of Kupffer Cells in Liver Disease
Kupffer cells, which have a characteristic morphology and a kind of phenotype, are the resident macrophages in liver, serve as the largest population mononuclear phagocytes in the body, and are localized in the periportal zone. They have phagocytosis capacity and release all kinds of cytokines, chemokines, and soluble biological mediators. Owing to the different functions of Kupffer cells, they play an important role in liver diseases. In this chapter, we review the role of Kupffer cells in infectious disease, fatty liver disease, liver fibrosis, liver ischemia-reperfusion injury, liver transplantation immunology, as well as liver cancer and metastases.
Kupffer cell infectious disease fatty liver disease fibrosis ischemia-reperfusion injury liver transplantation immunology liver cancer metastases
Kupffer cells (KCs), as the largest population mononuclear phagocytes in the body, account for 80–90% of the total number of natural macrophages and 20% of the liver nonparenchymal cells . They form a self-renewing pool of organ-resident macrophages independent of the myeloid monocyte compartment and derive from resident stem cells which originate from the fetal yolk sac before [2–4]. Other studies also found that KCs derived from embryonic progenitors colonize the tissues before birth [5–11], but with the growth of mouse, bone marrow-derived monocytes will fill up additional macrophage niches that become available, competing with the resident population. This situation occurs in the liver and spleen, but not in the brain and lung .
KCs have a characteristic morphology with amoeboid lamellipodia and an irregular surface containing many microvilli , located at the luminal side of liver sinusoidal endothelium or the lamellipodia extended into the Disse space through the fenestrae. This is an ideal position for their main function in the liver. This state can filter the blood that enters the liver from both the portal vein and the hepatic artery, which is an important part of the cellular immunity system of the mammalia (Figure 1). So, the structure of KCs plays a role in the mutual coordination and influence of liver parenchymal cells and other nonparenchymal cell functions and makes up these cells’ important versatile constituents of the liver [14–16]. Now, according to the function of KCs, they could be distinguished as two groups: the one with higher phagocytosis capacity and the other with preference toward cytokines and chemokines production [17, 18]. Some studies found that there were large KCs in rats. They are localized in the periportal zone and have increased phagocytosis and increased production of biological mediators. These large KCs can be identified by the expression of CD163, also described as ED2 antigen, which is a scavenger receptor . KCs (Table 1) can also be identified by the expression of CD68 (ED-1); they were called small KCs in rats. The general macrophage marker F4/80 or by ED-1 was expressed on the surface of mice KCs, which is present in all KCs regardless of their location . In mice, KCs can be distinguished from monocytes among the F4/80+ cells as Ly6C low CD11b low-cell population [21, 22]. Additionally, macrophages are functionally grouped into two classes, M1 and M2. M1 (termed classically activated) macrophages are pro-inflammatory and could produce pro-inflammatory cytokines and chemokines, while the M2 (termed alternatively activated) macrophages are suppressive and involved in cellular repair . According to this situation, KCs as one kind of macrophages also have these functions and play a fundamental role in homeostasis and diseases . KCs also have a unique KCs gene Clec4f to distinguish with other macrophage; Clec4F has been previously described as a KCs-specific marker [25–27].
Origin Marker PRR PAMP DAMP Immunogenic Polarization of macrophages
Rat Derived from the fetal yolk sack and embryonic progenitors colonize the tissues. Liver-resident Express Clec4F gene CD68/ED1 CD163/ED2 Scavengers receptors (CDl3, CD14, CDl5, CD68, CD163) Mannose receptors Fc receptors (CD64, CD32, CDl6) Complement receptor (CR1, CR3, CR4) I region-associated antigen TLR1-TLR9 NLR MHC-II CD80 CD86 PDL-1 (CD274) M1 Pro-inflammatory antitumoral
Mouse F4/80 CD68 CD11blow TLR1-TLR9 NLR RLR M2 Anti-inflammatory Immune suppressive protumoral
Human CD68 CD14 TLR2 TLR3 TLR4 NLR
This table is used for KC identification and major surface receptors and moleculars involved in the function in human, mouse, and rat.
Schematic representation of the liver microanatomical structure and Kupffer cell localization in lower magnification.
In vivo, under steady condition, the KCs are resting situation; they play a role in eliminating macromolecules, immune complexes, toxins, and degenerated cells from circulation. Pattern recognition receptors (PRRs) on the KCs are the main factor to eliminate the debris, toxins, and insoluble macromolecules, such as scavengers receptors (CDl3, CD14, CDl5, and CD68, CD163), mannose receptors, Fc receptors (including CD64, CD32, and CDl6), complement receptor (including the complement receptor L, complement receptor 3, and complement receptor 4), I region-associated antigen, which are able to bind to toxins lipopolysaccharide (LPS), immune complexes, or opsonized cells . Since KCs reside in the liver sinusoids in large numbers and are adherent to the endothelial cells, they are able to sample the blood entering the liver from the gut as well as from the main circulation. KCs also could remove the senescent or damaged erythrocytes. In this process, following phagocytosis and hemolysis, KCs could express HO (including HO-1, HO-2, and HO-3) to degrade hemoglobin, which is part of erythrocytes component. HO-1 catalyzes the degradation of heme into iron, biliverdin, and carbon monoxide, which are all considered to be hepatoprotective at low quantities under steady-state conditions [29, 30].
Pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) were two kinds of PRRs to express on the surface of KCs. They included multiple families, such as Toll-like, RIG-like, and NOD-like receptors (TLR, RLR, and NLR, respectively), and C-type lectin receptors (CLR) . Mouse KCs can express TLR1-TLR9, all of which appear to be functional . Human KCs, so far, have only been described to express TLR2, TLR3, and TLR4 [33, 34]. Furthermore, in the Listeria monocytogenes (Lm) infection model, mouse KCs are shown to express RIG-like receptor I . Hepatocytes and CD68+ liver mononuclear cells (presumably KCs) express NLRC2 (NOD2) . When the KCs were activated by the emergence of endotoxins and harmful exogenous particles from the portal vein and circulation, their functions were enhanced. They could produce all kinds of cytokines and chemokines significantly. In the presence of TLR ligands, such as LPS and CpG, the CD14-positive KCs were stimulated by TLR4, which activates the intracellular signal pathway via myeloid differentiation factor 88 (MyD 88), resulting in NF-κB activation to produce the pro-inflammation cytokines IL-6, TNF-α, IL-1β, ICAM-1, VCAM-1, and VAP-1 , and the CD14 expression on KCs is increased . CD14-transgenic mice that overexpress CD14 on monocytes have increased sensitivity to LPS . As a receptor of dsRNA, TLR3 on KCs is one of the primary triggers in the defense of viral diseases. TLR3 activation induces the strongest IFN-γ response. KCs were activated presumably due to the induction of IL-12 in the absence of IL-10 coproduction, which was observed upon TLR2 and TLR4 ligation . Activation of TLR7 triggers the secretion of type I interferons and activation of subsequent genes encoding CXCL10, CXCL11, Mx1 (antiviral G-Protein), CCL2 (also known as MCP-1), also secretion of IL-10, leading to enhanced viral clearance . TLR9 activation on KCs attenuates inflammation by the secretion of IL-10, suppressing the activation of infiltrating monocyte-derived macrophages in mice. This finding supports a dual role of TLR9 engagement, which depends on the target T-cell type . LPS, DNA, SFA, amyloid cholesterol, cathepsin κ, and reactive oxygen species (ROS) and so on have been suggested as NLPR3 activators, which comprise the NOD-like receptor NLRP3, the apoptosis-associated speck-like protein containing a caspase recruitment domain, and the effector molecule pro-caspase inflammation .
KCs likely derived from infiltrating monocytes express MHC-II antigens and costimulatory molecules (CD80 and CD86), which can present foreign antigens to the reactive T cells, induced T cell responses, and thus conferred tolerance to induce regulatory T cells in immune response . IL-10 and PDL-1 (also known as CD274) participated in the immune tolerance, which reduce the antigen-presenting capacity of KCs by downregulating the expression of MHC molecules and costimulators, but without strongly affecting the scavenger function of KCs.
KCs not only can interact with T cells but can also interact with many cellular components in the liver. For instance, KCs can initiate the recruitment of other monocytes to the liver in case of injuries, which is important for liver regeneration, and they also interact with hepatic stellate cells (HSCs) to play a role in liver diseases and repair [43, 44]. TLR4 signal on KCs indirectly silences patrolling NK cells by MYD88-dependent IL-10 secretion, whereas TLR2 or TLR3 induces IL-18 and IL-1β, leading to NK-cell activation in liver inflammation . Traditionally, M1 macrophage phenotype is marked by the release of pro-inflammatory cytokines like TNF-κ, IL-1, and IL-12. Alternative activation of M2 phenotype is more heterogeneous, as different stimuli are main to release anti-inflammation cytokines (such as IL-10). Typically, the increased expression of arginase 1, the secretion of immune-modulatory cytokines (such as IL-10 and TGF-κ), and the involvement in tissue repair phase are considered as indicators of M2 macrophage differentiation. Different origin of the cells together with the functional plasticity of macrophages can explain the phenotypic and functional heterogeneity of KCs observed upon different triggers of liver pathology [46, 47]. On the basis of these concepts, in the next sections, we summarize the role of KCs to various diseases involving the liver, in particular infectious disease, fatty liver disease, liver fibrosis and cirrhosis, ischemia and reperfusion (I/R) injury, liver cancer as well as liver transplantation immunology (Figure 2).
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