Liver macrophages: Friend or foe during hepatitis B infection?

Faure-Dupuy, Suzanne; Durantel, David; Lucifora, Julie

doi:10.1111/liv.13884

Cited by 29 publications

(29 citation statements)

References 94 publications

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“…(89,90) Several reviews pondered beneficial versus detrimental roles of macrophages during liver injury. (91)(92)(93)(94) A generally accepted view is that proinflammatory macrophages, derived from MoMFs, are required for activating regenerative mechanisms but may increase tissue injury through uncontrolled inflammation while restorative macrophages promote inflammation resolution and tissue repair but are also implicated in aberrant tissue repair mechanisms, namely fibrosis and cancer. (95,96) In opposition to the old dogma that macrophage-mediated inflammation is generally detrimental, a recent paper demonstrated that blocking Ly6C + monocyte recruitment by using a chemokine receptor CCR2 antagonist delayed hepatitis B virus clearance in mice while it was enhanced by KC depletion using clodronate-loaded liposomes.…”

Section: Multifaceted Roles Of Macrophages During Liver Injury and Rementioning

confidence: 99%

Liver Macrophages: Old Dogmas and New Insights

2019

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Inflammation is a hallmark of virtually all liver diseases, such as liver cancer, fibrosis, nonalcoholic steatohepatitis, alcoholic liver disease, and cholangiopathies. Liver macrophages have been thoroughly studied in human disease and mouse models, unravelling that the hepatic mononuclear phagocyte system is more versatile and complex than previously believed. Liver macrophages mainly consist of liver-resident phagocytes, or Kupffer cells (KCs), and bone marrow-derived recruited monocytes. Although both cell populations in the liver demonstrate principal functions of macrophages, such as phagocytosis, danger signal recognition, cytokine release, antigen processing, and the ability to orchestrate immune responses, KCs and recruited monocytes retain characteristic ontogeny markers and remain remarkably distinct on several functional aspects. While KCs dominate the hepatic macrophage pool in homeostasis ("sentinel function"), monocyte-derived macrophages prevail in acute or chronic injury ("emergency response team"), making them an interesting target for novel therapeutic approaches in liver disease. In addition, recent data acquired by unbiased large-scale techniques, such as single-cell RNA sequencing, unraveled a previously unrecognized complexity of human and murine macrophage polarization abilities, far beyond the old dogma of inflammatory (M1) and anti-inflammatory (M2) macrophages. Despite tremendous progress, numerous challenges remain in deciphering the full spectrum of macrophage activation and its implication in either promoting liver disease progression or repairing injured liver tissue. Being aware of such heterogeneity in cell origin and function is of crucial importance when studying liver diseases, developing novel therapeutic interventions, defining macrophage-based prognostic biomarkers, or designing clinical trials. Growing knowledge in gene expression modulation and emerging technologies in drug delivery may soon allow shaping macrophage populations toward orchestrating beneficial rather than detrimental inflammatory responses. (Hepatology Communications 2019;3:730-743). T he liver is the largest solid organ and exerts vital metabolic functions. Liver diseases leading to liver cirrhosis or cancer are increasingly challenging for public health, the current trend being an augmentation of such diseases mainly caused by changes in alimentation and life habits. (1) Liver diseases are various by nature in terms of etiologies, chronicity, and chances of recovery. However, one constant feature is the presence of liver inflammation, and most remarkably, there is an apparent compulsory association of inflammation with a poor outcome for patients. (2-6) Liver macrophages are included in the mononuclear phagocyte system and are renown cornerstones in most if not all inflammation-related liver disorders due to their ability to respond to a seemingly infinite

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Section: Multifaceted Roles Of Macrophages During Liver Injury and Rementioning

confidence: 99%

Liver Macrophages: Old Dogmas and New Insights

2019

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“…This effect was strengthened as the hepatic stellate cells further activated and disappeared when the CCL2/CCR2 axis was inhibited by INCB. On the one hand, M2 macrophage relieve liver damage caused by in ammatory reactions, and on the other hand, they accelerate the immune surveillance disorder under cirrhotic condition by secreting immunosuppressive cytokines [4], promoting vascular regeneration and tissue reconstruction [12]. What's more, M2 macrophages show a relatively weak antigen presentation, and secrete IL-10, TGF-β and other cytokines which are bene cial to the survival and sustained activation of aHSCs [34].…”

Section: Disscussionmentioning

confidence: 99%

“…Macrophages featured for strong plasticity [8] can differentiate into both pro-brotic and anti-brotic macrophages responding to different conditions [9,10]. They could exert two opposed functions by produce pro-in ammation or pro-brotic factors in different circumstances [10][11][12][13]. Generally, classically activated macrophages (M1) usually secrete pro-in ammatory cytokines that exert anti-infective effects.…”

Section: Introductionmentioning

confidence: 99%

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Shi

Zheng

Jiang

et al. 2020

Preprint

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Background: Growing evidence indicates that activated hepatic stellate cells (aHSCs) play unexpected roles in regulating immune cells’ function during liver fibrosis. Macrophages feature with inducible plasticity according to the circumstances while patrol for potential pathogens. However, studies seldom investigate whether and how the aHSCs regulate the phenotype and function of macrophages during liver fibrosis. Methods: 96 patients with different stages of liver fibrosis were involved in our study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and CD163 were detected by immunohistochemistry, and the relationship among CD163, CCL2, and fibrosis scores were explored. We co-cultured the aHSCs and THP-1-derived M0-type macrophages (M0MФ) to observe whether aHSCs modulate the expression of CD163 on macrophages in vitro. Furthermore, we treated the M0MФ with aHSCs’ supernatant and investigated the production of CCL2 in aHSCs by ELISA and immunofluorescence assay. To explore whether CCL2/CCR2 axis plays a crucial role in macrophage phenotypic changes during liver fibrosis, we used recombinant CCL2 and its specific receptor antagonist. Moreover, we employed LX2 system to confirm our results. Results: We found that hepatic M2 macrophages (CD163+) infiltration increased in different stages of liver fibrosis (F0-1: 34.95±18.12; F2-3: 77.57±32.48; F4: 99.62±40.84, F0-1 vs. F2-3, P<0.001; F2-3 vs. F4, P=0.074). After in vitro co-cultured with aHSCs, the macrophages expressed higher levels of CD163 (29.5±6.1% vs. 2.7±1.1%) as well as CD206 (28.0±4.2% vs. 2.4±1.2%) compared with the control. Then we found aHSC supernatant up-regulated the expression of CD163 (26.1±2.8%) and CD206 (25.8±3.8%) on macrophages independently. We noted aHSCs’ supernatant contained a high level of CCL2, which increased dramatically while TGF-β stimulation. Meanwhile, CCL2 staining score increased with the progress of fibrosis ( N: 23.26±13.85; F1: 4 8.56±19.18; F2: 58.25±16.24; F3: 81.32±18.48; F4: 110.93±24.75). Intriguingly, CCL2 significantly up-regulated the expression of CD163 (27.6±7.0%) and CD206 (26.5±5.1%) on macrophages besides inducing their aggregation. Results were confirmed with LX2 co-culture system. Conclusions: (1) The expression of M2 macrophage marker CD163 increased significantly during the progress of liver fibrosis and associated with fibrosis severity. (2) AHSCs can recruit macrophages and induce their M2 phenotypic transformation through CCL2/CCR2 pathway.

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“…TLRs, especially TLR2, are thought to play vital roles in recognizing virions and mediating the antiviral immune response during HBV infection (38,39). Although an in vitro assay demonstrated that HBcAg could be recognized by TLR2, resulting in macrophage activation, it is questionable whether core proteins are normally enveloped in virions within HBVinfected hepatocytes and can barely be detected in the peripheral blood, which should prevent HBcAg from being detected by TLR2 expressed on liver macrophages (40). Nonetheless, once the death of HBV-infected hepatocytes occurs, HBc proteins released from these cells may be subsequently captured by liver macrophages via TLR2 detection (16).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Core Antigen Impairs the Polarization While Promoting the Production of Inflammatory Cytokines of M2 Macrophages via the TLR2 Pathway

Zhang

Yang

et al. 2020

Front. Immunol.

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Although several evidences suggesting the vital roles that innate immunity plays in the persistence and elimination of chronic hepatitis B virus (CHB) infection, the exact mechanism is still complicated. Here, we successfully polarized monocytes derived from healthy human peripheral blood mononuclear cells (PBMCs) into M1/M2 macrophages and detected the effects of hepatitis B core antigen (HBcAg) on the polarization and function of macrophages via the Toll-like receptor (TLR) 2 signaling pathway. The results showed that HBcAg had a negligible impact on M1 polarization, while it effectively impaired M2 polarization and promoted the production of pro-inflammatory cytokines such as IL-6 and TNF-α. Additionally, HBcAg treatment increased TLR2 expression on M2 macrophages and TLR2 blockade abolished the effects of HBcAg on the impaired phenotype and pro-inflammatory cytokine productions of M2 macrophages. Signaling pathway analysis revealed that the nuclear factor κB (NF-κB) pathway, the downstream of TLR2, was upregulated upon HBcAg treatment in both M1 and M2 macrophages. Furthermore, a CD8 + T-macrophage coculture system implied that compared with PBS stimulation, HBcAg-stimulated M2 macrophages regained their ability to activate CD8 + T cells with higher secretion of IFN-γ. Finally, we found impaired expression of M2-related molecules and increased levels of pro-inflammation cytokines in M2 macrophages from CHB patients upon HBcAg stimulation. In conclusion, these results imply a favorable role of HBcAg in the establishment of a pro-inflammatory microenvironment by macrophages, which may suggest a potential therapeutic strategy of HBcAg-induced macrophage activation in CHB infection.

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Liver macrophages: Friend or foe during hepatitis B infection?

Abstract: The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over

Cited by 29 publications

References 94 publications

Liver Macrophages: Old Dogmas and New Insights

Liver Macrophages: Old Dogmas and New Insights

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Hepatitis B Core Antigen Impairs the Polarization While Promoting the Production of Inflammatory Cytokines of M2 Macrophages via the TLR2 Pathway

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