Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics

Liaskou, Evaggelia; Zimmermann, Henning W.; Li, Ka-Kit; Oo, Ye Htun; Suresh, Shankar; Stamataki, Zania; Qureshi, Omar; Lalor, Patricia F.; Shaw, J; Syn, Wing–Kin; Curbishley, Stuart M.; Adams, David H.

doi:10.1002/hep.26016

Cited by 212 publications

(218 citation statements)

References 31 publications

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“…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). However, we did not find evidence of liver damage at this early stage after infection.…”

Section: Discussioncontrasting

confidence: 54%

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: Discussioncontrasting

confidence: 54%

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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“…Activation of Kupffer cells and recruitment of monocyte/macrophages are key events governing initiation, perpetuation, and resolution of fibrosis. The influx of monocytes into the liver gives rise to inflammatory profibrogenic GR1 hi (Ly6C hi ) macrophages, expressing high levels of CD11b and F4/80 (38,49). The important role of Kupffer cells and infiltrating macrophages in the initiation and progression of fibrosis has been extensively characterized, using pharmacological or conditional genetic ablation of monocytes/macrophages, in mice with ongoing liver injury (14,30).…”

Section: Innate Immune Cellsmentioning

confidence: 99%

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Mallat

Lotersztajn

2013

American Journal of Physiology-Cell Physiology

193

220

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Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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“…The CD14 1/dim CD16 1 non-classical monocytes are regarded as the mature and pro-inflammatory subset of monocytes. 8,25,26 Increased numbers of CD14…”

Section: Discussionmentioning

confidence: 99%

An unbalanced PD-L1/CD86 ratio in CD14++CD16+ monocytes is correlated with HCV viremia during chronic HCV infection

Zheng

Liang

et al. 2014

Cell Mol Immunol

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Circulating monocyte subsets with distinct functions play important roles in hepatitis C virus (HCV) infection. However, the mechanisms have not been well studied. In this study, we analyzed the distributions and phenotypic characteristics of three circulating monocyte subsets-CD14 11 CD16 2 , CD14 11 CD16 1 and CD14 1/dim CD16 1 -in chronic HCV-infected patients, HCV spontaneous resolvers and healthy controls, and we evaluated the possible link between HCV viremia and disease progression. Our results indicated that the frequency of the CD14 11 CD16 1 monocyte subset was decreased, and negatively correlated with HCV RNA and core antigen levels during chronic HCV infection. PD-L1 expression and the PD-L1/CD86 ratio in CD1411 CD16 1 monocytes were higher during chronic HCV infection than in spontaneous HCV resolvers and healthy controls. The PD-L1/CD86 ratio positively correlated with HCV viral load and core antigen levels. Finally, PD-L1 was significantly increased, while cytokine secretions were dramatically decreased upon Toll-like receptor (TLR) ligand binding and HCV JFH-1stimulation. These findings indicates the compromised immune status of the CD14 11 CD161 monocytes during chronic HCV infection and provides new insights into the specific role of the CD14 11 CD161 monocytes and their significance in chronic HCV infection. 1 It has been estimated that 85% of HCV-infected individuals experience persistent infection, and about 20% of the persistently infected individuals develop liver cirrhosis and hepatocellular carcinoma.2,3 It has also been reported that about 20% of HCV-infected individuals had cleared the virus and were classified as spontaneous HCV resolvers. 4 The persistence of HCV infection indicates that the virus has evolved mechanisms to evade host immunity, including both innate and adaptive immunity, of which monocytes have received little attention. 3,[5][6][7] The characteristics and roles of the different monocyte subsets in chronic HCV infection and spontaneous HCV resolvers remain largely unknown.

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Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics

Cited by 212 publications

References 31 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

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

An unbalanced PD-L1/CD86 ratio in CD14++CD16+ monocytes is correlated with HCV viremia during chronic HCV infection

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