Kupffer Cells - An Overview

Introduction:

The liver is the largest unique vital organ in the human body. The liver is a multifunctional organ. It removes toxins from the human body, maintains healthy blood sugar levels, regulates blood clotting, and performs more than five hundred functions. The liver mainly consists of hepatocytes; other cells of the liver are the stellate fat-storing cells (HSCs), the liver sinusoidal endothelial cells (LSECs), and the Kupffer cells (KCs). These cells spatiotemporally cooperate to shape, increase and maintain liver function.

What Are Kupffer Cells?

Residing macrophages of the liver are Kupffer cells; these are phagocytic cells. Inside the liver sinusoids, Kupffer cells perform the function as a response to tissue damage and antigen presentation. They mainly reside in the lumen of hepatic sinusoids and account for 80 % to 90 % of colonized macrophages. Kupffer cells have the capacity for self-renewal that rarely migrate from the liver and play an important role in maintaining hemostasis. Upon liver damage, Kupffer cells get activated, releasing a good deal of inflammatory cytokines, small proteins secreted by cells, and chemokines (signaling proteins released by cells).

What Is the Function Performed by Kupffer Cells?

These star-shaped macrophages in the lining of the liver sinusoids (microscopic blood channels) are phagocytic, capable of ingesting other cells and foreign particles. They also store hemosiderin (iron-containing pigment) so that its availability for the production of hemoglobin (oxygen-transporting component of blood) is done.

Where Is the Kupffer Cell-Derived From?

Kupffer cells are derived from the circulating monocytes. In the mononuclear phagocyte system, bone marrow-derived monocytes in the blood migrate into various tissues and transform into tissue macrophages. One such tissue macrophage is Kupffer cells; it has a self-renewal capacity.

What Is the Role of Kupffer Cells in Hemoglobin Degradation?

• Scavenger receptors clear malformed blood cells by Kupffer cells and tissue macrophages in the spleen.

• During the lifespan of red blood cells, 20 % of hemoglobin is lost by shedding hemoglobin-containing vesicles, and Kupffer cells rapidly remove these vesicles from circulation.

• Kupffer cells express scavenger receptors CD163, involved in the clearance and endocytosis of hemoglobin-haptoglobin complexes protecting tissue from free hemoglobin-mediated oxidant injury.

• Kupffer cell gives two isoforms, HO-1 and HO-2; HO-1 inhibits bilirubin formation; the breakdown of heme yields iron, biliverdin, and carbon monoxide.

• HO-1-derived vasorelaxant carbon monoxide seems to protect the hepatic circulation under stress conditions.

• Kupffer cells, CD163, and HO-1 together form a protective system that coherently upregulates during inflammatory conditions to enhance hemoglobin clearance and heme degradation.

What Is the Role of Kupffer Cells in Immune Response?

• The liver is actively tolerogenic and plays a key role in preventing generalized inflammation by eliminating circulating CD8+T cells.

• The neutrophil ingestion by Kupffer cells has significant implications for the development and expression of adaptive immunity of the liver.

• Kupffer cell recovers chronically accepted hepatic allografts that have a great ability to induce apoptosis of alloreactive T-cells. In contrast, prolonged administration of these in hepatic allografts occurs in the acute rejection models.

• Apoptotic neutrophils ingested by kupffer cells greatly impact the developing antigen-specific CD4+ or CD8+ T-cell mediated immunity in the liver.

What Is the Role of Kupffer Cells in Liver Injury?

Kupffer cells play an important role in the pathogenesis of different liver diseases like:

• Alcoholic liver disease.

• Non-alcoholic fatty liver.

• Liver failure due to Acetaminophen intoxication.

• Iron and copper toxicity.

• Ischemia-reperfusion injury during a liver transplant.

In detail :

1. Acetaminophen Toxicity: The analgesic or antipyretic overdose produces centrilobular hepatic necrosis, which leads to acute liver failure. Depletion of intracellular glutathione and increased generation of reactive oxygen and nitrogen critical pathomechanisms. Kupffer cell activation, iNOS induction, and subsequent formation of NO are major determinants of peroxynitrite formation and, consequently, Acetaminophen toxicity.

2. Ischaemia-Reperfusion Injury: It is a major factor responsible for morbidity associated with liver resection or after liver transplantation. Excessive inflammatory response induces Kupffer cells; these accumulate LPS (lipopolysaccharide) during the non-hepatic phase of liver transplantation through the activation of complement factors.

3. Alcoholic Liver Disease: Liver macrophages play a key role in the pathogenesis of this disease; the early stages of the intragastric ethanol infusion model attenuate the depletion of Kupffer cells with gadolinium chloride. The activation of Kupffer cells increases the permeability of the gut to endotoxins.

4. Non-alcoholic Fatty Liver Disease(NAFLD): Lipid accumulation in the liver leads to subacute hepatic inflammation, and downstream cytokine production may cause insulin resistance, which is associated with the activation of Kupffer cells. Kupffer cells seem essential in developing steatohepatitis (advanced stage of nonalcoholic fatty liver disease) and liver fibrosis.

What Is the Significance of Kupffer Cells in Liver Metastases?

• Liver metastases are a frequent complication of gastrointestinal malignancies.

• From initial detachment of the primary tumor, entry into the portal circulation, and entrapment of metastatic cells in liver sinusoids.

• Kupffer cells are the first cells that come in contact with disseminated gut tumor cells and the lining of hepatic sinusoids.

• Kupffer cells depletion before tumor cells can hinder a drastic increase in tumor development in the liver.

• Kupffer cells can prevent the outgrowth of the liver in malignant conditions but can contribute to proliferation once the liver metastasis is started.

Conclusion:

Kupffer cells are closely involved in the response activity of the liver in infections, toxins, ischemia, resection, and stress. Kupffer cells release various products like prostanoids, nitric oxide, reactive oxygen species, and various cytokines upon activation. The interaction between Kupffer cells and leukocytes is an important mechanism of host defense for liver regeneration and the development of immune tolerance after liver transplantation. Kupffer cells are the first line of defense for organisms. Stellate cells (quiescent fibroblasts that normally reside in sinusoidal walls within the subendothelial space of Disse) present in sinusoidal space are characterized morphologically by the presence of large fat droplets in their cytoplasm and play a vital role in the storage of vitamin A and can be transformed into proliferative, fibrogenic, and contractile myofibroblasts.