Regulation of Kupffer Cell Activation
Timothy R. Billiar, Ronald D. Curran in Hepatocyte and Kupffer Cell Interactions, 2017
The liver occupies a critical role in the host response to sepsis. When significant liver dysfunction occurs the mortality is 40 to 50% with isolated hepatic failure1 and exceeds 90% if other organs have also failed.2,3 Kupffer cells are the largest reservoir of fixed-tissue macrophages and are quantitatively the most important for removal of circulating bacteria, endotoxin, and other circulating microbial debris.4,5 Quantitatively, Kupffer cell phagocytosis is the most important route of bacterial clearance in sepsis.5 Kupffer cells, like other macrophages throughout the body, are derived from a common bone marrow precursor cell.6,7 Despite their common origin, macrophages are adapted to function in different microenvironments. We hypothesize that many of the differences in the functional attributes of different macrophagelike cells may be due to differences in their “activation state”.8
The accessory organs: Pancreas, liver and gallbladder
Paul Ong, Rachel Skittrall in Gastrointestinal Nursing, 2017
The hepatic diverticulum produces the parenchyma (functional cells) of the liver, specialised liver cells called hepatocytes, and the epithelial lining of the biliary tract. The hepatocytes are arranged into a series of plates in the mesenchyme tissue (from mesodermal cells) of the transverse septum. The differentiating glandular tissue, as well as forming plates, is also bathed with vitelline and umbilical veins to form hepatic sinusoids. These form canal-type structures that are lined by the hepatocytes. The splanchnic mesenchyme (structure created during embryogenesis) in the transverse septum also forms the stroma, the connective tissue that makes up the liver capsule (or Gilson's capsule), the falciform ligament (attaches the liver to the abdominal and diaphragm wall), and the hematopoietic (blood-forming) tissue of the liver. Mature Kupffer cells are macrophages found in the lumen of hepatic sinusoids. Primitive macrophages arise in the yolk sac and then differentiate into foetal macrophages. These then enter the blood circulation and migrate to the developing liver. The connective tissue and smooth muscle of the biliary tract also develop from this mesenchyme. The formation of bile begins in week 12. Breast milk is already emulsified so bile will not be needed until the infant starts to take solid food.
Pathology of the Liver: Functional and Structural Alterations of Hepatocyte Organelles Induced by Cell Injury
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
The resident liver macrophages (Kupffer cells) (Figure 1) are important in the clearing of necrotic hepatocytes by phagocytosis and rapid degradation of cellular fragments present in the sinusoids or in the space of Disse (Glaumann and Marzella, 1981). Kupffer cells are also active in the uptake and killing of bacteria and in the phagocytosis and in the lysis of tumor cells (Xu et al., 1984). The distribution and activity of Kupffer cells over the liver lobule is heterogeneous. Cells near the portal veins are more abundant, larger, and have higher phagocytic capacity (Sleyster and Knook, 1982). If the phagocytic capacity of the Kupffer cells is enhanced, the ability of the liver to resist many types of insults increases (Loegering and Blumenstock, 1985). However, activation of the Kupffer cells may also increase the susceptibility of the liver to some types of injury such as that induced by endotoxin. It has been proposed that the release of toxic oxygen species and lysosomal enzymes from the Kupffer cells may participate in the induction of hepatocyte injury. It has been shown that phagocytizing macrophages release lysosomal enzymes to the extracellular milieu (Dean et al., 1979; Nichols, 1982). In sum the Kupffer cells perform a very important function, but the potential for hepatocyte damage exists because of release of enzyme and of toxic oxygen species from the Kupffer cells.
Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease
Published in Expert Opinion on Therapeutic Targets, 2022
Tea Lund Laursen, Anders Mellemkjær, Holger Jon Møller, Henning Grønbæk, Konstantin Kazankov
In the present review, we bring an update on the role of macrophages for NAFLD disease development and progression, describing the role of resident macrophages viz. Kupffer cells and the recruitment of monocytes and macrophages to the liver. Activation of macrophages during NAFLD development and progression can be initiated by several stimuli including DAMPS and PAMPS with specific cross talk of the liver with the gut microbiome and adipose tissue. It is expected that a better characterization of the gut microbiome of importance for macrophage activation and NAFLD development may lead to interventions targeting the gut microbiota resulting in less macrophage activation inflammation and fibrosis. Along the same lines, DAMPS or molecules and pathways involved in the development of DAMPS may be future targets. In addition, disturbances of both hepatic and adipose tissues insulin sensitivity have been linked to macrophage activation, suggesting that interventions including pharmaceuticals that improve insulin resistance and the metabolic syndrome may ameliorate NAFLD. This effect may occur directly but also indirectly through macrophage activation.
Using imaging to study inflammatory platelet–leukocyte interactions in vivo
Published in Platelets, 2020
Olivia Susanto, Michael J. Hickey
Interactions between platelets and Kupffer cells are also observed during bacterial infection [35,59]. In the absence of infection, platelets “patrol” the liver by consistently undergoing transient interactions with Kupffer cells, a process dependent on platelet expression of CD42/GPIb. Following infection with blood-borne bacteria, Kupffer cells capture bacteria from the bloodstream. Platelets then adhere to the Kupffer cell, forming an aggregate that can eventually encapsulate the captured bacterium. Platelet depletion or absence of CD42/GPIb significantly decreases mouse survival in this infection model, demonstrating the importance of platelets for bacterial clearance [35]. More recently, the ability of platelets to independently migrate and mechanically probe their environment has been demonstrated by in vivo imaging, revealing that platelets can use these abilities to collect and bundle fibrin-bound bacteria to facilitate bacterial clearance [48].
Non-alcoholic fatty liver disease (NAFLD) models in drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Banumathi K. Cole, Ryan E. Feaver, Brian R. Wamhoff, Ajit Dash
The co-culture of hepatocytes with liver NPCs, including hepatic stellate cells (HSCs), liver resident inflammatory cells (e.g. kupffer cells, macrophages), and liver sinusoidal endothelial cells, has been shown to improve the overall hepatocyte function and health by providing paracrine and mechanical support [68–71]. Queiscent HSCs reside in the space of Disse and secrete a number of hepatic mitogens, such as hepatocyte growth factor and epidermal growth factor, that can improve hepatic function [68,72–74]. During liver injury and progression of NASH, these transdifferentiate into myofibroblastic-like cells that migrate to sites of injury and amplify the inflammatory response through antigen presentation and its secretion of cytokines and chemokines, mediating autophagy and apoptosis, and producing reactive oxygen species (reviewed in Weiskirchen et al. 2014, Friedman et al. 2008 [75,76]). Kupffer cells, which make up 15% of liver cells, are liver resident macrophages found in the hepatic sinusoid that phagocyte pathogens from the portal vein and arterial circulation and prevent gut-derived pathogenic antigens from passing into the hepatic parenchyma. During hepatic insult or metabolic fluctuations of lipids, these cells rapidly expand and secrete cytokines and chemokines (reviewed in Duarte et al. 2015 [77]). Thus, the addition of NPCs provides an opportunity to evaluate disease-related endpoints that are not primarily driven by the hepatocytes, such as inflammatory cytokine expression or stellate cell activation, hallmark features of NASH and fibrosis [78].
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