TNFα-Mediated Liver Destruction by Kupffer Cells and Ly6Chi Monocytes during Entamoeba histolytica Infection

Helk, Elena; Bernin, Hannah; Ernst, Thomas; Ittrich, Harald; Jacobs, Thomas; Heeren, Joerg; Tacke, Frank; Tannich, Egbert; Lotter, Hannelore

doi:10.1371/journal.ppat.1003096

Cited by 81 publications

(85 citation statements)

References 50 publications

(67 reference statements)

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“…On the other hand, LPS-induced inflammatory monocytes do not increase their ability to produce or express cytokines or chemokines but enhance their endocytosis potential. In mouse studies, TNF production by intrahepatic inflammatory monocytes has been associated with liver damage (29,30). Similarly, in patients with chronic inflammatory and fibrotic liver diseases, inflammatory monocyte-derived TNF, among other proinflammatory cytokines and chemokines, has been shown to be profibrogenic (45).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to their systemic function, opposing roles during sterile toxin-induced liver inflammation have been identified. For example, in acetaminophen-induced hepatitis, hepatic inflammatory monocytes are endocytic and display an immunoregulatory phenotype (27), while in concanavalin A and CCl4 hepatitis, they promote Th1 cell proliferation and produce proinflammatory cytokines such as TNF and interleukin-6 (IL-6) (28)(29)(30). Due to the shortage of specific animal models, the role of these innate immune cells during virus-induced liver disease is less explored.…”

Section: Importancementioning

confidence: 99%

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Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

Movita

Garde

Biesta

et al. 2015

J Virol

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Due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro-and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80 high -Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis. IMPORTANCEInsights into how the immune system deals with hepatitis B virus (HBV) and HCV are scarce due to the lack of adequate animal model systems. This knowledge is, however, crucial to developing new antiviral strategies aimed at eradicating these chronic infections. We model virus-host interactions during the initial phase of liver inflammation 24 h after inoculating mice with LCMV. We show that infected Kupffer cells are rapidly outnumbered by infiltrating inflammatory monocytes, which secrete proinflammatory cytokines but are less phagocytic. Nevertheless, these recruited inflammatory monocytes start to resemble Kupffer cells on a transcript level. The specificity of these cellular changes for virus-induced liver inflammation is corroborated by demonstrating opposite functions of monocytes after LPS challenge. Overall, this demonstrates the enormous functional and genetic plasticity of infiltrating monocytes and identifies them as an important target cell for future treatment regimens. V iral hepatitis, predominantly caused by the hepatitis B and C viruses (HBV and HCV, respectively), is a global health burden (1, 2). Although clearance of HBV and HCV infection is ...

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Section: Discussionmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

Movita

Garde

Biesta

et al. 2015

J Virol

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“…More TNF-␣ production was shown to correlate with E. histolytica diarrhea in children, and blocking of TNF-␣ with monoclonal antibodies reduced inflammation and intestinal damage from amebic infections in mice (5,6). TNF-␣ was also recently shown to mediate the tissue destruction seen in amebic liver abscesses (7).…”

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confidence: 99%

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

et al. 2014

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bThe host inflammatory response contributes to the tissue damage that occurs during amebic colitis, with tumor necrosis factor alpha (TNF-␣) being a key mediator of the gut inflammation observed. Mammalian macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the exacerbation of a wide range of inflammatory diseases, including colitis. We identified a MIF gene homolog in the Entamoeba histolytica genome, raising the question of whether E. histolytica MIF (EhMIF) has proinflammatory activity similar to that of mammalian MIF. In this report, we describe the first functional characterization of EhMIF. Antibodies were prepared against recombinantly expressed EhMIF and used to demonstrate that EhMIF is expressed as a 12-kDa protein localized to the cytoplasm of trophozoites. In a manner similar to that of mammalian MIF, EhMIF interacted with the MIF receptor CD74 and bound to macrophages. EhMIF induced interleukin-6 (IL-6) production. In addition, EhMIF enhanced TNF-␣ secretion by amplifying TNF-␣ production by lipopolysaccharide (LPS)-stimulated macrophages and by inhibiting the glucocorticoid-mediated suppression of TNF-␣ secretion. EhMIF was expressed during human infection, as evidenced by the presence of anti-EhMIF antibodies in the sera of children living in an area where E. histolytica infection is endemic. Anti-EhMIF antibodies did not cross-react with human MIF. The ability of EhMIF to modulate host macrophage function may promote an exaggerated proinflammatory immune response and contribute to the tissue damage seen in amebic colitis.

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“…Selective depletion of KCs using liposomeentrapped clodronate or the inhibition of monocytes infiltration using CCR22/2 mice revealed that KCs and inflammatory Ly-6Chi monocytes, through producing TNF-α, are the main effector cells responsible for liver destruction during ALA [112].…”

Section: Liver Infection By Parasitesmentioning

confidence: 99%

The Biological Function of Kupffer Cells in Liver Disease

Ma¹,

Yang²,

He³

et al. 2017

Biology of Myelomonocytic Cells

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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.

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TNFα-Mediated Liver Destruction by Kupffer Cells and Ly6Chi Monocytes during Entamoeba histolytica Infection

Cited by 81 publications

References 50 publications

Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

The Biological Function of Kupffer Cells in Liver Disease

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