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Millian DE, Arroyave E, Wanninger TG, Krishnan S, Bao D, Zhang JR, Rao A, Spratt H, Ferguson M, Chen V, Stevenson HL, Saldarriaga OA. Alterations in the hepatic microenvironment following direct-acting antiviral therapy for chronic hepatitis C. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.17.25321289. [PMID: 40034770 PMCID: PMC11875275 DOI: 10.1101/2025.02.17.25321289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Background and aims. The first direct-acting antivirals (DAAs) to treat the viral hepatitis C (HCV) became available in 2011. Despite numerous clinical studies of patient outcomes after treatment, few have evaluated changes in the liver microenvironment. Despite achieving sustained virologic response (SVR), patients may still experience adverse outcomes like cirrhosis and hepatocellular carcinoma. By comparing gene and protein expression in liver biopsies collected before and after treatment, we sought to determine whether specific signatures correlated with disease progression and adverse clinical outcomes. Methods. Biopsies were collected from 22 patients before and after DAA treatment. We measured ∼770 genes and used multispectral imaging with custom machine learning algorithms to analyze phenotypes of intrahepatic macrophages (CD68, CD14, CD16, MAC387, CD163) and T cells (CD3, CD4, CD8, CD45, FoxP3). Results. Before DAA treatment, patients showed two distinct gene expression patterns: one with high pro-inflammatory and antiviral gene expression and another with weaker expression. Patients with adverse outcomes exhibited significantly (p<0.05) more inflammatory activity and had more advanced fibrosis stages in their baseline biopsies than those with liver disease resolution. Patients who achieved SVR had significantly decreased liver enzymes, reduced inflammatory scores, and restored type 1 interferon pathways similar to controls. However, after DAA treatment, patients with persistently high gene expression (67%, pre-hot) still had significantly worse outcomes (p<0.049) despite achieving SVR. A persistent lymphocytic infiltrate was observed in a subset of these patients (76.5%). After therapy, anti-inflammatory macrophages (CD16+, CD16+CD163+, CD16+CD68+) increased, and T cell heterogeneity was more pronounced, showing a predominance of helper and memory T cells (CD3+CD45RO+, CD4+CD45RO+, CD3+CD4+CD45RO+). Conclusions. Patients who have more inflamed livers and more advanced fibrosis before DAA treatment should be closely followed for the development of adverse outcomes, even after achieving SVR. We can enhance patient risk stratification by integrating gene and protein expression profiles with clinical data. This could identify those who may benefit from more intensive monitoring or alternative therapeutic approaches, inspiring a new era of personalized patient care. Lay Summary Direct-acting antiviral (DAA) therapy has dramatically improved the treatment of chronic HCV, making it curable for most people. This study determined gene and protein expression differences in the liver before and after treatment of HCV. These results will lead to a deeper understanding of the changes in the hepatic immune microenvironment with and without the virus present in the liver in hopes of improving patient surveillance, prognosis, and outcome in the future.
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Seurre C, Roca Suarez AA, Testoni B, Zoulim F, Grigorov B. After the Storm: Persistent Molecular Alterations Following HCV Cure. Int J Mol Sci 2024; 25:7073. [PMID: 39000179 PMCID: PMC11241208 DOI: 10.3390/ijms25137073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
The development of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has revolutionized the management of this pathology, as their use allows viral elimination in a large majority of patients. Nonetheless, HCV remains a major public health problem due to the multiple challenges associated with its diagnosis, treatment availability and development of a prophylactic vaccine. Moreover, HCV-cured patients still present an increased risk of developing hepatic complications such as hepatocellular carcinoma. In the present review, we aim to summarize the impact that HCV infection has on a wide variety of peripheral and intrahepatic cell populations, the alterations that remain following DAA treatment and the potential molecular mechanisms implicated in their long-term persistence. Finally, we consider how recent developments in single-cell multiomics could refine our understanding of this disease in each specific intrahepatic cell population and drive the field to explore new directions for the development of chemo-preventive strategies.
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Affiliation(s)
- Coline Seurre
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (C.S.); (A.A.R.S.); (B.T.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Armando Andres Roca Suarez
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (C.S.); (A.A.R.S.); (B.T.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (C.S.); (A.A.R.S.); (B.T.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Fabien Zoulim
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (C.S.); (A.A.R.S.); (B.T.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
- Hospices Civils de Lyon, 69002 Lyon, France
| | - Boyan Grigorov
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (C.S.); (A.A.R.S.); (B.T.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
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Yap YJ, Wong PF, AbuBakar S, Sam SS, Shunmugarajoo A, Soh YH, Misbah S, Ab Rahman AK. The clinical utility of CD163 in viral diseases. Clin Chim Acta 2023; 541:117243. [PMID: 36740088 DOI: 10.1016/j.cca.2023.117243] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Macrophage activation and hypercytokinemia are notable presentations in certain viral infections leading to severe disease and poor prognosis. Viral infections can cause macrophage polarization into the pro-inflammatory M1 or anti-inflammatory M2 phenotype. Activated M1 macrophages usually restrict viral replication whereas activated M2 macrophages suppress inflammation and promote tissue repair. In response to inflammatory stimuli, macrophages polarize to the M2 phenotype expressing hemoglobin scavenger CD163 surface receptor. The CD163 receptor is shed as the soluble form, sCD163, into plasma or tissue fluids. sCD163 causes detoxification of pro-oxidative hemoglobin which produces anti-inflammatory metabolites that promote the resolution of inflammation. Hence, increased CD163 expression in tissues and elevated circulatory levels of sCD163 have been associated with acute and chronic inflammatory diseases. CD163 and other macrophage activation markers have been commonly included in the investigation of disease pathogenesis and progression. This review provides an overview of the involvement of CD163 in viral diseases. The clinical utility of CD163 in viral disease diagnosis, progression, prognosis and treatment evaluation is discussed.
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Affiliation(s)
- Yi-Jing Yap
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Sazaly AbuBakar
- Tropical Infectious Diseases Research and Education Centre (TIDREC), Universiti Malaya, 50603 Kuala Lumpur, Malaysia; World Health Organization Collaborating Centre for Arbovirus Reference and Research (Dengue and Severe Dengue) MAA-12, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Sing-Sin Sam
- Tropical Infectious Diseases Research and Education Centre (TIDREC), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Anusha Shunmugarajoo
- Medical Department, Tengku Ampuan Rahimah Hospital, 41200 Klang, Selangor, Malaysia
| | - Yih-Harng Soh
- Centers for Disease Control and Prevention Unit, Central Melaka District Health Office, Jalan Bukit Baru, 75150 Melaka, Malaysia
| | - Suzana Misbah
- Biological Security and Sustainability Research Group (BIOSES), Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - Ahmad Kashfi Ab Rahman
- Department of Medicine (Infectious Disease Unit), Sultanah Nur Zahirah Hospital, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Terengganu, Malaysia
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Wang C, Ma C, Gong L, Guo Y, Fu K, Zhang Y, Zhou H, Li Y. Macrophage Polarization and Its Role in Liver Disease. Front Immunol 2022; 12:803037. [PMID: 34970275 PMCID: PMC8712501 DOI: 10.3389/fimmu.2021.803037] [Citation(s) in RCA: 335] [Impact Index Per Article: 111.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.
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Affiliation(s)
- Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuqin Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Gantzel RH, Kjær MB, Laursen TL, Kazankov K, George J, Møller HJ, Grønbæk H. Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis. Front Med (Lausanne) 2021; 7:615599. [PMID: 33490096 PMCID: PMC7820116 DOI: 10.3389/fmed.2020.615599] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/11/2020] [Indexed: 12/19/2022] Open
Abstract
Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.
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Affiliation(s)
| | - Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 2020; 319:G151-G156. [PMID: 32597708 DOI: 10.1152/ajpgi.00128.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.
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Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Alex Lund Laursen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Laursen TL, Sandahl TD, Kazankov K, George J, Grønbæk H. Liver-related effects of chronic hepatitis C antiviral treatment. World J Gastroenterol 2020; 26:2931-2947. [PMID: 32587440 PMCID: PMC7304101 DOI: 10.3748/wjg.v26.i22.2931] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.
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Affiliation(s)
- Tea L Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Thomas D Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, Sydney NSW 2145, Australia
- University of Sydney, Sydney NSW 2145, Australia
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
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Nielsen MC, Hvidbjerg Gantzel R, Clària J, Trebicka J, Møller HJ, Grønbæk H. Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure. Cells 2020; 9:cells9051175. [PMID: 32397365 PMCID: PMC7290463 DOI: 10.3390/cells9051175] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
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Affiliation(s)
- Marlene Christina Nielsen
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.C.N.); (H.J.M.)
| | - Rasmus Hvidbjerg Gantzel
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, Denmark;
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain; (J.C.); (J.T.)
- Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain
| | - Jonel Trebicka
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain; (J.C.); (J.T.)
- Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, 60323 Frankfurt, Germany
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.C.N.); (H.J.M.)
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, Denmark;
- Correspondence: ; Tel.: +45-21-67-92-81
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Alharthi J, Latchoumanin O, George J, Eslam M. Macrophages in metabolic associated fatty liver disease. World J Gastroenterol 2020; 26:1861-1878. [PMID: 32390698 PMCID: PMC7201150 DOI: 10.3748/wjg.v26.i16.1861] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/10/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries. The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis, hepatocellular carcinoma, liver transplantation, and death, but also to extrahepatic complications including cardiovascular disease, diabetes and chronic kidney disease. The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development. This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis, inflammation, fibrosis, and hepatocellular carcinoma, as well as for the extra-hepatic manifestations of MAFLD. We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes, hepatic stellate cells, and adipose tissue. We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
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Affiliation(s)
- Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
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Laursen TL, Siggaard CB, Kazankov K, Sandahl TD, Møller HJ, Tarp B, Kristensen LH, Laursen AL, Leutscher P, Grønbaek H. Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C. J Viral Hepat 2020; 27:28-35. [PMID: 31502741 DOI: 10.1111/jvh.13204] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/14/2019] [Accepted: 08/22/2019] [Indexed: 12/12/2022]
Abstract
Sofosbuvir-based direct-acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy-one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir-based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8 mg/L, P < .0001), whereas the change in sMR was more subtle (0.37 vs 0.30 mg/L, P < .0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3 kPa, P < .0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P < .0001), suggestive of fibrosis regression. The GEC improved at follow-up (all: 1.74 vs 1.98 mmol/min), mainly at 12 weeks post-treatment, both in patients with cirrhosis (n = 56) and those with advanced liver fibrosis (n = 15) (P < .001). The CRT improved at one-year follow-up (1.86 vs 2.09, P = .04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.
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Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Britta Tarp
- Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark
| | | | - Alex Lund Laursen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Leutscher
- Centre for Clinical Research, North Denmark Regional Hospital, Hjørring, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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11
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Read SA, Wijaya R, Ramezani-Moghadam M, Tay E, Schibeci S, Liddle C, Lam VWT, Yuen L, Douglas MW, Booth D, George J, Ahlenstiel G. Macrophage Coordination of the Interferon Lambda Immune Response. Front Immunol 2019; 10:2674. [PMID: 31798594 PMCID: PMC6878940 DOI: 10.3389/fimmu.2019.02674] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 10/30/2019] [Indexed: 12/18/2022] Open
Abstract
Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes.
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Affiliation(s)
- Scott A Read
- Blacktown Medical School, Western Sydney University, Blacktown, NSW, Australia.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Ratna Wijaya
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Mehdi Ramezani-Moghadam
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Enoch Tay
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Steve Schibeci
- Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Vincent W T Lam
- Department of Upper Gastrointestinal Surgery, Westmead Hospital, Westmead, NSW, Australia.,Discipline of Surgery, University of Sydney, Sydney, NSW, Australia
| | - Lawrence Yuen
- Department of Upper Gastrointestinal Surgery, Westmead Hospital, Westmead, NSW, Australia.,Discipline of Surgery, University of Sydney, Sydney, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia.,Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
| | - David Booth
- Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Golo Ahlenstiel
- Blacktown Medical School, Western Sydney University, Blacktown, NSW, Australia.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia.,Blacktown Hospital, Western Sydney Local Health District (WSLHD), Blacktown, NSW, Australia
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12
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Lidofsky A, Holmes JA, Feeney ER, Kruger AJ, Salloum S, Zheng H, Seguin IS, Altinbas A, Masia R, Corey KE, Gustafson JL, Schaefer EA, Hunt PW, Deeks S, Somsouk M, Chew KW, Chung RT, Alatrakchi N. Macrophage Activation Marker Soluble CD163 Is a Dynamic Marker of Liver Fibrogenesis in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection. J Infect Dis 2018; 218:1394-1403. [PMID: 29868909 PMCID: PMC6151081 DOI: 10.1093/infdis/jiy331] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 05/31/2018] [Indexed: 12/12/2022] Open
Abstract
Background Coinfection with human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV)-related liver fibrosis. Macrophages are triggered during both viral infections and are critical in liver inflammation/fibrogenesis. Liver fibrosis strongly associates with serum soluble CD163 (sCD163, a macrophage activation marker); comprehensive evaluation in HIV/HCV coinfection is lacking. Methods We retrospectively analyzed sCD163 (enzyme-linked immunosorbent assay) and hepatic CD163 (immunofluorescent CD163/CD68 costaining) in patients infected with HIV/HCV, HCV, or HIV, pre- and post-antiviral therapy. Results sCD163 was significantly higher in HIV/HCV compared to either monoinfection, and decreased following successful antiviral therapy, although did not fully normalize. In HIV/HCV, sCD163 was associated with necroinflammation, Ishak fibrosis scores, and noninvasive fibrosis scores. We observed a novel trend whereby sCD163 levels progressively increase with increasing Ishak fibrosis score, peaking at stage 4, above which levels plateaued. Periportal CD163+ macrophage frequency was also higher with increasing fibrosis score. When stratified by fibrosis stage, sCD163 levels were higher in HIV/HCV than HCV but only in individuals with mild to moderate fibrosis. Conclusions In HIV/HCV, increasing sCD163 levels accompanied periportal CD163+ macrophage enrichment in mild to moderate fibrosis, but not in established cirrhosis, suggesting that sCD163 is a dynamic biomarker of fibrogenesis rather than accumulated fibrosis. Our findings implicate HIV-related macrophage activation in accelerated fibrosis progression in HIV/HCV coinfection.
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Affiliation(s)
- Anna Lidofsky
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jacinta A Holmes
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Eoin R Feeney
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- HIV Molecular Research Group, University College of Dublin, Ireland
| | - Annie J Kruger
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shadi Salloum
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hui Zheng
- Biostatistics Center, Massachusetts General Hospital, Boston
| | - Isabel S Seguin
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Akif Altinbas
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ricard Masia
- Department of Pathology, Massachusetts General Hospital, Boston
| | - Kathleen E Corey
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jenna L Gustafson
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Esperance A Schaefer
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Peter W Hunt
- Department of Medicine, University of California, San Francisco
| | - Steven Deeks
- Department of Medicine, University of California, San Francisco
| | - Ma Somsouk
- Department of Medicine, University of California, San Francisco
| | - Kara W Chew
- Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles
| | - Raymond T Chung
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nadia Alatrakchi
- Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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13
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Lund Laursen T, Brøckner Siggard C, Kazankov K, Damgaard Sandahl T, Møller HJ, Ong A, Douglas MW, George J, Tarp B, Hagelskjaer Kristensen L, Lund Laursen A, Hiramatsu A, Nakahara T, Chayama K, Grønbaek H. Rapid and persistent decline in soluble CD163 with successful direct-acting antiviral therapy and associations with chronic hepatitis C histology. Scand J Gastroenterol 2018; 53:986-993. [PMID: 29987961 DOI: 10.1080/00365521.2018.1481996] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163-levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first-generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response.
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Affiliation(s)
- Tea Lund Laursen
- a Department of Hepatology & Gastroenterology , Aarhus University Hospital , Aarhus , Denmark
| | | | - Konstantin Kazankov
- a Department of Hepatology & Gastroenterology , Aarhus University Hospital , Aarhus , Denmark
| | - Thomas Damgaard Sandahl
- a Department of Hepatology & Gastroenterology , Aarhus University Hospital , Aarhus , Denmark
| | - Holger Jon Møller
- b Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - Adrian Ong
- c Storr Liver Centre , Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney , Australia
| | - Mark W Douglas
- c Storr Liver Centre , Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney , Australia
| | - Jacob George
- c Storr Liver Centre , Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney , Australia
| | - Britta Tarp
- d Diagnostic Centre , Silkeborg Regional Hospital , Silkeborg , Denmark
| | | | - Alex Lund Laursen
- f Department of Infectious Diseases , Aarhus University Hospital , Aarhus , Denmark
| | - Akira Hiramatsu
- g Department of Gastroenterology and Metabolism , Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima , Japan
| | - Takashi Nakahara
- g Department of Gastroenterology and Metabolism , Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- g Department of Gastroenterology and Metabolism , Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima , Japan.,h Laboratory for Digestive Diseases , RIKEN Center for Integrative Medical Sciences , Hiroshima , Japan
| | - Henning Grønbaek
- a Department of Hepatology & Gastroenterology , Aarhus University Hospital , Aarhus , Denmark
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14
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Soluble CD163 and soluble CD14 plasma levels but not cellular HIV-DNA decrease during successful interferon-free anti-HCV therapy in HIV-1-HCV co-infected patients on effective combined anti-HIV treatment. Med Microbiol Immunol 2018. [PMID: 29523966 DOI: 10.1007/s00430-018-0538-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Soluble CD163, soluble CD14 and cellular HIV-1-DNA levels reflect two different aspects of HIV infection: immune activation and the reservoir of infected cells. The aim of this study was to describe their relationships in a cohort of HIV-HCV co-infected patients successfully treated for both HCV and HIV infections. Fifty-five patients were recruited and studied prior to the start of direct-acting antivirals (DAAs) (T0), at week 12 of DAA treatment (T1) and 24 weeks after T0 (T2). The subjects were classified as having undetectable plasma HIV viraemia (UV) or low-level viraemia (LLV) in the 18 months before T2. Plasma levels of sCD163 and of sCD14 were comparable in patients with UV and in subjects with LVL at T0, T1 and T2. The HIV DNA level was positively correlated with LLV but not with sCD163 and sCD14 levels; these two markers of inflammation were positively correlated (p = 0.017). Soluble CD163 and sCD14 decreased over time from T0 to T2 (p = 0.000 and p = 0.034, respectively). In conclusion, the significant decrease in sCD163 and sCD14 levels in patients cured of HCV infection, regardless of the presence of LLV, suggests a main role for HCV in immune activation in HIV-HCV co-infected patients.
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15
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Mascia C, Vita S, Zuccalà P, Marocco R, Tieghi T, Savinelli S, Rossi R, Iannetta M, Pozzetto I, Furlan C, Mengoni F, Mastroianni CM, Vullo V, Lichtner M. Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon. PLoS One 2017. [PMID: 28636655 PMCID: PMC5499435 DOI: 10.1371/journal.pone.0179400] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background and aims Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10
(CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported
in HCV infection. The aim of this study was to compare, sCD163 and sCD14
levels in HCV-infected patients undergoing direct acting antiviral
(DAA)-containing regimens with or without interferon (IFN). Methods sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma
samples from 25 HCV-infected patients undergoing IFN-based treatment plus
telaprevir or boceprevir and 28 HCV infected subjects treated with DAA
IFN-free regimens. Twenty-five healthy donors (HD) were included as
controls. Results At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected
patients than in HD. CXCL10 and sCD163 levels were significantly decreased
in responder (R) patients who achieved sustained virological response (SVR),
with both IFN-based and IFN-free regimens, while they were persistently
elevated in non-responders (NR) patients who stopped IFN-based treatments
because of failure or adverse events. Conversely, sCD14 levels were
apparently unchanged during therapy, but at the end of treatment the levels
reached normal ranges. Comparing the two regimens, the extent of CXCL10
reduction was more pronounced in patients undergoing DAA IFN-free therapies,
whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were
significantly higher in NR than in R patients, while in the IFN-free
treatment group also patients with high sCD163 plasma levels obtained SVR.
At the end of therapy, even if the biomarkers were largely decreased, their
levels remained significantly higher compared to HD. Only in the early
fibrosis stages, sCD163 values tended to normalize. Conclusions These results indicate that IFN-free regimens including newer DAA induce an
early and marked decrease in circulating inflammatory biomarkers. However,
the full normalization of biomarkers was not obtained, especially in
patients with advanced fibrosis, thus underlying the need for a treatment in
the early stages of HCV infection.
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Affiliation(s)
- Claudia Mascia
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- * E-mail:
| | - Serena Vita
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Paola Zuccalà
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Raffaella Marocco
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Tiziana Tieghi
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Stefano Savinelli
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Raffaella Rossi
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Marco Iannetta
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Irene Pozzetto
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Caterina Furlan
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Fabio Mengoni
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
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16
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Tentillier N, Etzerodt A, Olesen MN, Rizalar FS, Jacobsen J, Bender D, Moestrup SK, Romero-Ramos M. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model. J Neurosci 2016; 36:9375-90. [PMID: 27605613 PMCID: PMC6601874 DOI: 10.1523/jneurosci.1636-16.2016] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 06/22/2016] [Accepted: 07/13/2016] [Indexed: 01/20/2023] Open
Abstract
UNLABELLED Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD. SIGNIFICANCE STATEMENT The immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant extent infiltrated in the neurodegenerating area of the brain. Specially designed liposomes targeted for the CD163 receptor were loaded with glucocorticoids and injected peripherally to modify the infiltrated CD163 cells toward an anti-inflammatory profile. This modification of the CD163 population resulted in a distinctive microglial response that correlated with decreased dopaminergic cell death and better motor performance.
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Affiliation(s)
- Noemie Tentillier
- CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and
| | | | - Mads N Olesen
- CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and
| | - F Sila Rizalar
- CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and
| | - Jan Jacobsen
- Department of Clinical Medicine, PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark, and
| | - Dirk Bender
- Department of Clinical Medicine, PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark, and
| | - Søren K Moestrup
- Department of Biomedicine, and Department of Cancer and Inflammation Research, Syddansk University, DK-5000 Odense, Denmark
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17
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Krämer B, Finnemann C, Sastre B, Lutz P, Glässner A, Wolter F, Goeser F, Kokordelis P, Kaczmarek D, Nischalke HD, Strassburg CP, Spengler U, Nattermann J. IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C. PLoS One 2016; 11:e0162068. [PMID: 27583440 PMCID: PMC5008784 DOI: 10.1371/journal.pone.0162068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/17/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used. RESULTS Following stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals. CONCLUSIONS Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.
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Affiliation(s)
- Benjamin Krämer
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Claudia Finnemann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Beatriz Sastre
- Department of Infectious Diseases, Institute for Health Research (IRYCIS), University Hospital Ramón y Cajal, Madrid, Spain
- AIDS Research Network (RIS-RETICS), Madrid, Spain
| | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Andreas Glässner
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Franziska Wolter
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Felix Goeser
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Pavlos Kokordelis
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Dominik Kaczmarek
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Hans-Dieter Nischalke
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Christian P. Strassburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research (DZIF), Bonn, Germany
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18
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High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy. Tumour Biol 2015; 37:7129-37. [PMID: 26662957 DOI: 10.1007/s13277-015-4593-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 12/03/2015] [Indexed: 02/07/2023] Open
Abstract
Salient studies have investigated the association between host inflammatory response and cancer. This study was conducted to test the hypothesis that peripheral absolute monocyte counts (AMC) could impart an increased risk of hepatocellular carcinoma (HCC) development in hepatitis C virus (HCV)-infected patients after a failed peginterferon/ribavirin (PR) combination therapy. A total of 723 chronic HCV-infected patients were treated with PR, of which 183 (25.3 %) patients did not achieve a sustained virological response (non-SVR). Post-treatment AMC values were measured at 6 months after end of PR treatment. Fifteen (2.8 %) of 540 patients with an SVR developed HCC during a median follow-up period of 41.4 months, and 14 (7.7 %) of 183 non-SVR patients developed HCC during a median follow-up of 36.8 months (log rank test for SVR vs. non-SVR, P = 0.002). Cox regression analysis revealed that post-treatment AFP level (HR 1.070; 95 % CI = 1.024-1.119, P = 0.003) and post-treatment aspartate aminotransferase (AST)-to-platelet ratio index (APRI) ≥0.5 (HR 4.401; 95 % CI = 1.463-13.233, P = 0.008) were independent variables associated with HCC development for SVR patients. For non-SVR patients, diabetes (HR 5.750; 95 % CI = 1.387-23.841, P = 0.016), post treatment AMC ≥370 mm(-3) (HR 5.805; 95 % CI = 1.268-26.573, P = 0.023), and post-treatment APRI ≥1.5 (HR 10.905; 95 % CI = 2.493-47.697, P = 0.002) were independent risks associated with HCC. In conclusion, post-treatment AMC has a role in prognostication of HCC development in HCV-infected patients who failed to achieve an SVR after PR combination therapy.
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