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Kupffer Cells in the Liver

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Kupffer cells are a critical component of the mononuclear phagocytic system and are central to both the hepatic and systemic response to pathogens. Kupffer cells are reemerging as critical mediators of both liver injury and repair. Kupffer cells exhibit a tremendous plasticity; depending on the local metabolic and immune environment, then can express a range of polarized phenotypes, from the proinflammatory M1 phenotype to the alternative/M2 phenotype. Multiple M2 phenotypes can be distinguished, each involved in the resolution of inflammation and wound healing. Here, we have provided an update on recent research that has contributed to the developing delineation of the contribution of Kupffer cells to different types of liver injury, with an emphasis on alcoholic and nonalcoholic liver diseases. These recent advances in our understanding of Kupffer cell function and regulation will likely provide new insights into the potential for therapeutic manipulation of Kupffer cells to promote the resolution of inflammation and enhance wound healing in liver disease. © 2013 American Physiological Society. Compr Physiol 3:785‐797, 2013.

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Figure 1. Figure 1.

Localization of Kupffer cells within the hepatic sinusoid in healthy and diseased liver. The Kupffer cell is located to the hepatic sinusoid and is therefore in close proximity to other cells in the sinusoid, including natural killer (NK) and natural killer T cells (NKT), as well as the liver sinusoidal endothelial cells (LSEC). Despite the barrier of the LSEC, Kupffer cell products, such as cytokines, chemokines, reactive nitrogen, and oxygen species, influence the activity of both stellate cells and hepatocytes.

Figure 2. Figure 2.

The complement anaphylatoxins activate Kupffer cells to express inflammatory cytokines and chemokines. Complement activation via the classical, lectin or alternative pathways culminates in the cleavage of C3. C3a and C5a, termed the anaphylatoxins, then interact with cognate receptors on the surface of macrophages. Interaction between Toll‐like receptor 4 (TLR4) and the anaphylatoxin receptors can exacerbate cytokine/chemokine production.

Figure 3. Figure 3.

Interactions between Kupffer cells and the regulation of hepatocyte proliferation in response to tissue injury: role of early growth response‐1. In acute carbon tetrachloride‐induced hepatoxicity, production of cytokines and other hepatoprotective factors is precisely controlled, both spatially and temporally. Absence of individual transcription factors, such as early growth response‐1 (Egr‐1), controlling these responses to injury results in an impaired hepatoproliferative response and an increased susceptibility to hepatoxicity (104, 105, 108).

Figure 1.

Localization of Kupffer cells within the hepatic sinusoid in healthy and diseased liver. The Kupffer cell is located to the hepatic sinusoid and is therefore in close proximity to other cells in the sinusoid, including natural killer (NK) and natural killer T cells (NKT), as well as the liver sinusoidal endothelial cells (LSEC). Despite the barrier of the LSEC, Kupffer cell products, such as cytokines, chemokines, reactive nitrogen, and oxygen species, influence the activity of both stellate cells and hepatocytes.

Figure 2.

The complement anaphylatoxins activate Kupffer cells to express inflammatory cytokines and chemokines. Complement activation via the classical, lectin or alternative pathways culminates in the cleavage of C3. C3a and C5a, termed the anaphylatoxins, then interact with cognate receptors on the surface of macrophages. Interaction between Toll‐like receptor 4 (TLR4) and the anaphylatoxin receptors can exacerbate cytokine/chemokine production.

Figure 3.

Interactions between Kupffer cells and the regulation of hepatocyte proliferation in response to tissue injury: role of early growth response‐1. In acute carbon tetrachloride‐induced hepatoxicity, production of cytokines and other hepatoprotective factors is precisely controlled, both spatially and temporally. Absence of individual transcription factors, such as early growth response‐1 (Egr‐1), controlling these responses to injury results in an impaired hepatoproliferative response and an increased susceptibility to hepatoxicity (104, 105, 108).

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Laura J. Dixon, Mark Barnes, Hui Tang, Michele T. Pritchard, Laura E. Nagy. Kupffer Cells in the Liver. Compr Physiol 2013, 3: 785-797. doi: 10.1002/cphy.c120026