Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

Lang, Philipp A.; Recher, Mike; Honke, Nadine; Scheu, Stefanie; Borkens, Stephanie; Gailus, Nicole; Krings, Caroline; Meryk, Andreas; Kulawik, Andreas; Cervantes-Barragán, Luisa; Rooijen, Nico van; Kalinke, Ulrich; Ludewig, Burkhard; Hengartner, Hans; Harris, Nicola L.; Häussinger, Dieter; Ohashi, Pamela S.; Zinkernagel, Rolf M.; Lang, Karl S.

doi:10.1002/hep.23640

Cited by 84 publications

(90 citation statements)

References 40 publications

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“…Previous studies showed an accumulation of LCMV particles in the liver within minutes after an intravenous challenge (37). In line with this, we observed a reproducible LCMV replication in the liver of mice inoculated 24 h earlier, reaching average titers of 2.27 ϫ 10 5 PFU/g of liver.…”

Section: Resultssupporting

confidence: 90%

“…Previous data from our group and others have shown that Kupffer cells from healthy mice are specialized phagocytes with only marginal cytokine production ex vivo under steady-state conditions (31) and that Kupffer cells are among the first to be infected with LCMV, thereby limiting viral spread (37)(38)(39). We studied here in detail the endocytic ability of F4/80 highKupffer cells and inflammatory monocytes during early LCMV infection.…”

Section: Resultsmentioning

confidence: 98%

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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: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 98%

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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“…Splenectomy did not affect serum HBsAg levels compared with the sham-operated group (Figure 4), a result that is consistent with previous studies showing that splenectomized mice exhibited normal viral clearance during lymphocytic choriomeningitis virus infection. 24 From these findings, we hypothesize that the liverdraining LNs can provide a functional substitute for the spleen in the induction of immune response, but that the spleen still primes an anti-HBV immune response when present during infection. This interpretation is supported by the observation of an anti-HBV specific immune response in the spleen in this mouse model (data unpublished).…”

Section: Induction Of Anti-hbv Responses In the Liver-draining Lnsmentioning

confidence: 87%

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

Zheng

Tian

2013

Cell Mol Immunol

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The lymphatic system is important in mounting an immune response to foreign antigens and tumors in humans and animal models. The liver produces a large amount of lymph, and its lymphatic system is divided into three major components: the portal, sublobular and superficial lymphatic vessels. Despite the fact that mice are the most commonly used laboratory animals, detailed descriptions of the anatomical location and function of the lymph nodes (LNs) that drain the liver are surprisingly absent. In this study, we found that the portal and celiac LNs adjacent to mouse liver were stained with Evans blue within 5-8 min. Enhanced green fluorescence protein (EGFP)-positive cells from the liver also drained into the two aforementioned LNs. These data indicate that the portal and celiac LNs drain the mouse liver. Lymphadenectomy of the identified liver-draining LNs resulted in hepatitis B virus (HBV) persistence in immunocompetent mice compared with the sham group. In addition, the frequencies of CD81 T cells and dendritic cells (DCs) increased significantly in the liver-draining LNs after hydrodynamic injection of HBV plasmid. Liver-draining LN cells in HBV plasmid-injected mice also showed significant antigen-specific proliferation in response to stimulation with recombinant hepatitis B core antigen in vitro. Adoptive transfer of these cells into Rag1 2/2 mice induced a reduction in the serum concentration of hepatitis B surface antigen (HBsAg) compared to liver-draining LN cells in uninjected mice. Altogether our data characterize the liver-draining LNs and provide evidence that the liver-draining LNs induce an anti-HBV-specific immune response responsible for HBV clearance.

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“…In many models of liver injury, hepatic macrophages themselves are involved in the pathogenesis of the liver damage (31). In other models, macrophages play a role in preventing severe hepatic immunopathology (32) or in limiting the severity of liver immunopathology (33). These particular mechanisms do not appear to play a significant role in our HBV model, as mice lacking macrophages or CXCL13/CXCR5 did not have a significant difference in liver injury, despite developing significantly different immune responses to HBV (Figures 3, 5, and 6).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Publicover¹,

Gaggar²,

Nishimura³

et al. 2013

J. Clin. Invest.

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Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

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Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

Cited by 84 publications

References 40 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

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

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