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Holger Jon Moller - One of the best experts on this subject based on the ideXlab platform.

  • the macrophage activation marker soluble CD163 is elevated and associated with liver disease phenotype in patients with wilson s disease
    Orphanet Journal of Rare Diseases, 2020
    Co-Authors: Emilie Glavind, Holger Jon Moller, Daniel Gotthardt, Jan Pfeiffenberger, Thomas Damgaard Sandahl, Teodora Bashlekova, Gro Linno Willemoe, Jane Preuss Hasselby, Karl Heinz Weiss, Hendrik Vilstrup
    Abstract:

    Macrophages play a significant role in liver disease development and progression. The macrophage activation marker soluble (s)CD163 is associated with severity and prognosis in a number of different acute and chronic liver diseases but has been only sparsely examined in Wilson’s disease (WD). We investigated sCD163 levels in patients with acute and chronic WD and hypothesized associations with liver disease phenotype and biochemical markers of liver injury. We investigated sCD163 in two independent cohorts of WD patients: 28 patients with fulminant WD from the US Acute Liver Failure (ALF) Study Group registry and 147 patients with chronic disease from a German WD registry. We included a control group of 19 healthy individuals. Serum sCD163 levels were measured by ELISA. Liver CD163 expression was determined by immunohistochemistry. In the ALF cohort, median sCD163 was 10-fold higher than in healthy controls (14.6(2.5–30.9) vs. 1.5(1.0–2.7) mg/L, p < 0.001). In the chronic cohort, median sCD163 was 2.6(0.9–24.9) mg/L. There was no difference in sCD163 according to subgroups based on initial clinical presentation, i.e. asymptomatic, neurologic, hepatic, or mixed. Patients with cirrhosis at the time of diagnosis had higher sCD163 compared with those without cirrhosis (3.0(1.2–24.9) vs. 2.3(0.9–8.0) mg/L, p < 0.001); and both cohorts significantly lower than the ALF patients. Further, sCD163 correlated positively with ALT, AST, GGT and INR (rho = 0.27–0.53); and negatively with albumin (rho = − 0.37), (p ≤ 0.001, all). We observed immunohistochemical CD163 expression in liver tissue from ALF patients. Although sCD163 is not specific for WD, it was elevated in WD patients, especially in those with ALF. Further, sCD163 was higher in patients with cirrhosis compared to patients without cirrhosis and associated with biochemical markers of liver injury and hepatocellular function. Thus, macrophage activation is evident in WD and associates with liver disease phenotype and biochemical parameters of liver disease. Our findings suggest that sCD163 may be used as a marker of liver disease severity in WD patients.

  • Circulating extracellular vesicle‐associated CD163 and CD206 in multiple myeloma
    European journal of haematology, 2020
    Co-Authors: Sarah L Kvorning, Morten Andersen, Marlene Christina Nielsen, Niels Frost Andersen, Marianne Hokland, Holger Jon Moller
    Abstract:

    OBJECTIVES Extracellular vesicles (EVs) are important for intercellular signalling in cancer. Tumour-associated macrophages, expressing the haemoglobin-haptoglobin and mannose receptors CD163 and CD206, are crucial for cancer progression. We recently identified CD163 on EVs in the circulation as a fraction of total soluble CD163 (sCD163). Here, we investigated the presence of CD163 and CD206-positive EVs (EV-CD163, EV-CD206) in patients with multiple myeloma (MM). METHODS We enrolled patients with MM (n = 32), monoclonal gammopathy of undetermined significance (MGUS) (n = 8) and healthy donors (n = 16). Plasma protein levels were determined by ELISA before and after vesicle precipitation. Monocytes were examined by flow cytometry, and leucocyte CD163 mRNA by qPCR. RESULTS Fractions of EV-CD163 and EV-CD206 were significantly elevated in patients with newly diagnosed MM (median = 39.8%, 76.5%, respectively) compared to patients with relapse (15.6%, P = .02, 42.5%, P = .003), remission (16.9%, P 

  • macrophage markers are poorly associated with liver histology in children with nonalcoholic fatty liver disease
    Journal of Pediatric Gastroenterology and Nutrition, 2018
    Co-Authors: Konstantin Kazankov, Anna Alisi, Holger Jon Moller, Rita De Vito, Soren Rittig, Birgitte Mahler, Valerio Nobili, Henning Gronbaek
    Abstract:

    OBJECTIVES We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P < 0.001). In the cross-sectional cohort, sCD163 only showed trends toward association with ballooning (rho = 0.14, P = 0.08) and portal inflammation (rho = 0.17, P = 0.08). sMR showed similar associations with liver histology. In the VSL#3 cohort, sCD163 correlated inversely with steatosis (rho = -0.35, P = 0.04), and lobular (rho = -0.57, P < 0.001) and portal inflammation (rho = -0.38, P = 0.02); sMR was not associated with any histological scores. Neither sCD163 nor sMR changed significantly during intervention, and without association with NAFLD resolution. CONCLUSIONS The macrophage activation markers sCD163 and sMR showed poor associations with liver histology in 2 different cohorts of children with biopsy-proven NAFLD, and none of the markers decreased during successful intervention. These results are in contrast with studies of adult NAFLD and may suggest a possibility of different roles for macrophages in the pathogenesis of adult and pediatric NAFLD.

  • Soluble Macrophage Mannose Receptor (sCD206/sMR) as a Biomarker in Human Immunodeficiency Virus Infection.
    The Journal of infectious diseases, 2018
    Co-Authors: Morten Andersen, Holger Jon Moller, Bo Langhoff Hønge, Sanne Jespersen, Candida Medina, David Da Silva Té, A. L. Laursen, Christian Wejse, Christian Erikstrup, Amabelia Rodrigues
    Abstract:

    Macrophages play important roles during human immunodeficiency virus (HIV) infection, reflected by changes in macrophage-activation biomarker soluble CD163 (sCD163). Here, we present data on the novel macrophage-activation biomarker soluble mannose receptor/CD206 (sCD206) in HIV infection. We investigated sCD206 blood levels at baseline and follow-up with/without antiretroviral therapy (ART), in 212 patients with HIV type 1 (HIV-1), HIV type 2 (HIV-2), or dual infection. At baseline, there was no difference in sCD206 level between HIV types, and sCD206 was unchanged at follow-up without ART. However, in contrast to sCD163, sCD206 levels decreased significantly for both HIV-1 and HIV-2, but not for HIV-1/2 patients, during ART. Further investigations are needed to establish sCD206 as a biomarker in HIV infection.

  • Macrophage Markers Are Poorly Associated With Liver Histology in Children With Nonalcoholic Fatty Liver Disease.
    Journal of Pediatric Gastroenterology and Nutrition, 2018
    Co-Authors: Konstantin Kazankov, Anna Alisi, Holger Jon Moller, Rita De Vito, Soren Rittig, Birgitte Mahler, Valerio Nobili, Henning Gronbaek
    Abstract:

    OBJECTIVES We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P 

Søren K. Moestrup - One of the best experts on this subject based on the ideXlab platform.

  • Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of 'soluble CD163' in plasma.
    Scientific reports, 2017
    Co-Authors: Anders Etzerodt, Holger Jon Moller, Morten Andersen, Ronan M. G. Berg, Ronni R. Plovsing, Magali Bebien, Mohamed Habbeddine, Toby Lawrence, Søren K. Moestrup
    Abstract:

    CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma 'soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting 'soluble CD163' in plasma may therefore add to the diagnostic and prognostic value.

  • Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of `soluble CD163' in plasma
    Scientific Reports, 2017
    Co-Authors: Anders Etzerodt, Holger J Møller, Ronan M. G. Berg, Ronni R. Plovsing, Morten N. Andersen, Magali Bebien, Mohamed Habbeddine, Toby Lawrence, Søren K. Moestrup
    Abstract:

    CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammationinducible TACE/ADAM17 enzyme. Accordingly, plasma `soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting `soluble CD163' in plasma may therefore add to the diagnostic and prognostic value.

  • plasma soluble CD163 level independently predicts all cause mortality in hiv 1 infected individuals
    The Journal of Infectious Diseases, 2016
    Co-Authors: Troels Bygum Knudsen, Holger Jon Moller, Søren K. Moestrup, Gideon Ertner, Janne Petersen, Jesper Eugenolsen, Gitte Kronborg, Thomas Benfield
    Abstract:

    BACKGROUND CD163, a monocyte- and macrophage-specific scavenger receptor, is shed as soluble CD163 (sCD163) during the proinflammatory response. Here, we assessed the association between plasma sCD163 levels and progression to AIDS and all-cause mortality among individuals infected with human immunodeficiency virus type 1 (HIV). METHODS Plasma sCD163 levels were measured in 933 HIV-infected individuals. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with mortality were computed by Cox proportional hazards regression. RESULTS At baseline, 86% were receiving antiretroviral treatment, 73% had plasma a HIV RNA level of <50 copies/mL, and the median CD4(+) T-cell count was 503 cells/µL. During 10.5 years of follow-up, 167 (17.9%) died. Plasma sCD163 levels were higher in nonsurvivors than in survivors (4.92 mg/L [interquartile range {IQR}, 3.29-8.65 mg/L] vs 3.16 mg/L [IQR, 2.16-4.64 mg/L]; P = .0001). The cumulative incidence of death increased with increasing plasma sCD163 levels, corresponding to a 6% or 35% increased risk of death for each milligram per liter or quartile increase, respectively, in baseline plasma sCD163 level (adjusted HR, 1.06 [95% CI, 1.03-1.09] and 1.35 [95% CI, 1.13-1.63], respectively). CONCLUSIONS Plasma sCD163 was an independent marker of all-cause mortality in a cohort of HIV-infected individuals, suggesting that monocyte/macrophage activation may play a role in HIV pathogenesis and be a target of intervention.

  • structural basis for inflammation driven shedding of CD163 ectodomain and tumor necrosis factor α in macrophages
    Journal of Biological Chemistry, 2014
    Co-Authors: Anders Etzerodt, Holger Jon Moller, Søren K. Moestrup, Mie Rostved Rasmussen, Pia Svendsen, Athena Chalaris, Jeanette Schwarz, Ian Galea
    Abstract:

    The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. This leads to release of soluble CD163 (sCD163) and bioactive TNF-α. Sequence comparison of the juxtamembrane region identified similar palindromic sequences in human CD163 (1044Arg-Ser-Ser-Arg) and proTNF-α (78Arg-Ser-Ser-Ser-Arg). In proTNF-α the Arg-Ser-Ser-Ser-Arg sequence is situated next to the previously established ADAM17 cleavage site. Site-directed mutagenesis revealed that the sequences harbor essential information for efficient cleavage of the two proteins upon ADAM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palindromic CD163 sequence in the juxtamembrane region. Mouse CD163 resisted endotoxin- and phorbol ester-induced shedding, and ex vivo analysis of knock-in of the Arg-Ser-Ser-Arg sequence in mouse CD163 revealed a receptor shedding comparable with that of human CD163. In conclusion, we have identified an essential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophages. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, underwent a modification that allows for an instant down-regulation of surface CD163 expression and inhibition of hemoglobin uptake. This regulatory modality seems to have coincided with the evolution of an enhanced hemoglobin-protecting role of the haptoglobin-CD163 system in primates.

  • serum soluble CD163 predicts risk of type 2 diabetes in the general population
    Clinical Chemistry, 2011
    Co-Authors: Holger Jon Moller, Søren K. Moestrup, Ruth Frikkeschmidt, Borge G Nordestgaard, Anne Tybjaerghansen
    Abstract:

    BACKGROUND: Activation of adipose tissue macrophages with concomitant low-grade inflammation is believed to play a central role in the development of type 2 diabetes. We tested whether a new macrophage-derived biomarker, soluble CD163 (sCD163), identifies at-risk individuals before overt disease has developed. METHODS: A prospective cohort study of 8849 study participants from the general population, the Copenhagen City Heart Study, was followed for 18 years for incidence of type 2 diabetes. Risk of disease was calculated according to age- and sex-adjusted percentile categories of serum sCD163 concentrations: 0%–33%, 34%–66%, 67%–90%, 91%–95%, and 96%–100%. RESULTS: A total of 568 participants developed type 2 diabetes. The cumulative incidence increased with increasing baseline sCD163 (trend P 70 years of age, serum sCD163 concentrations in the top 5% group predicted an absolute 10-year risk of type 2 diabetes of 29% and 36% vs 7% and 8% in the lowest percentile group. Equivalent values in women were 19% and 24% vs 4% and 5%. CONCLUSIONS: Increased concentrations of sCD163 predict increased risk of type 2 diabetes in the general population and may be useful for identification of high-risk overweight individuals.

Anders Etzerodt - One of the best experts on this subject based on the ideXlab platform.

  • Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of 'soluble CD163' in plasma.
    Scientific reports, 2017
    Co-Authors: Anders Etzerodt, Holger Jon Moller, Morten Andersen, Ronan M. G. Berg, Ronni R. Plovsing, Magali Bebien, Mohamed Habbeddine, Toby Lawrence, Søren K. Moestrup
    Abstract:

    CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma 'soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting 'soluble CD163' in plasma may therefore add to the diagnostic and prognostic value.

  • Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of `soluble CD163' in plasma
    Scientific Reports, 2017
    Co-Authors: Anders Etzerodt, Holger J Møller, Ronan M. G. Berg, Ronni R. Plovsing, Morten N. Andersen, Magali Bebien, Mohamed Habbeddine, Toby Lawrence, Søren K. Moestrup
    Abstract:

    CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammationinducible TACE/ADAM17 enzyme. Accordingly, plasma `soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting `soluble CD163' in plasma may therefore add to the diagnostic and prognostic value.

  • structural basis for inflammation driven shedding of CD163 ectodomain and tumor necrosis factor α in macrophages
    Journal of Biological Chemistry, 2014
    Co-Authors: Anders Etzerodt, Holger Jon Moller, Søren K. Moestrup, Mie Rostved Rasmussen, Pia Svendsen, Athena Chalaris, Jeanette Schwarz, Ian Galea
    Abstract:

    The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. This leads to release of soluble CD163 (sCD163) and bioactive TNF-α. Sequence comparison of the juxtamembrane region identified similar palindromic sequences in human CD163 (1044Arg-Ser-Ser-Arg) and proTNF-α (78Arg-Ser-Ser-Ser-Arg). In proTNF-α the Arg-Ser-Ser-Ser-Arg sequence is situated next to the previously established ADAM17 cleavage site. Site-directed mutagenesis revealed that the sequences harbor essential information for efficient cleavage of the two proteins upon ADAM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palindromic CD163 sequence in the juxtamembrane region. Mouse CD163 resisted endotoxin- and phorbol ester-induced shedding, and ex vivo analysis of knock-in of the Arg-Ser-Ser-Arg sequence in mouse CD163 revealed a receptor shedding comparable with that of human CD163. In conclusion, we have identified an essential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophages. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, underwent a modification that allows for an instant down-regulation of surface CD163 expression and inhibition of hemoglobin uptake. This regulatory modality seems to have coincided with the evolution of an enhanced hemoglobin-protecting role of the haptoglobin-CD163 system in primates.

  • tumor necrosis factor α converting enzyme tace adam17 mediates ectodomain shedding of the scavenger receptor CD163
    Journal of Leukocyte Biology, 2010
    Co-Authors: Anders Etzerodt, Holger Jon Moller, Søren K. Moestrup, Maciej Bogdan Maniecki, Kirsten Moller
    Abstract:

    CD163 is expressed specifically in the monocyte/macrophage lineage, where it mediates uptake of haptoglobin-hemoglobin complexes, leading to metabolism of the oxidative heme molecule. Shedding of the CD163 ectodomain from the cell surface produces a sCD163 plasma protein, and a positive correlation is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity.

Anne Tybjaerghansen - One of the best experts on this subject based on the ideXlab platform.

  • serum soluble CD163 predicts risk of type 2 diabetes in the general population
    Clinical Chemistry, 2011
    Co-Authors: Holger Jon Moller, Søren K. Moestrup, Ruth Frikkeschmidt, Borge G Nordestgaard, Anne Tybjaerghansen
    Abstract:

    BACKGROUND: Activation of adipose tissue macrophages with concomitant low-grade inflammation is believed to play a central role in the development of type 2 diabetes. We tested whether a new macrophage-derived biomarker, soluble CD163 (sCD163), identifies at-risk individuals before overt disease has developed. METHODS: A prospective cohort study of 8849 study participants from the general population, the Copenhagen City Heart Study, was followed for 18 years for incidence of type 2 diabetes. Risk of disease was calculated according to age- and sex-adjusted percentile categories of serum sCD163 concentrations: 0%–33%, 34%–66%, 67%–90%, 91%–95%, and 96%–100%. RESULTS: A total of 568 participants developed type 2 diabetes. The cumulative incidence increased with increasing baseline sCD163 (trend P 70 years of age, serum sCD163 concentrations in the top 5% group predicted an absolute 10-year risk of type 2 diabetes of 29% and 36% vs 7% and 8% in the lowest percentile group. Equivalent values in women were 19% and 24% vs 4% and 5%. CONCLUSIONS: Increased concentrations of sCD163 predict increased risk of type 2 diabetes in the general population and may be useful for identification of high-risk overweight individuals.

Henning Gronbaek - One of the best experts on this subject based on the ideXlab platform.

  • Soluble CD163 correlates with lipid metabolic adaptations in type 1 diabetes patients during ketoacidosis
    Wiley, 2019
    Co-Authors: Mads Svart, Holger J Møller, Nikolaj Rittig, Niels Møller, Henning Gronbaek
    Abstract:

    Abstract Introduction Diabetic ketoacidosis (DKA) is associated with inflammation and increased lipolysis. The macrophage activation marker, soluble CD163 (sCD163), is associated with obesity, non‐alcoholic fatty liver disease and type 2 diabetes. We aimed to investigate whether sCD163 correlates with key elements of lipolysis in type 1 diabetes patients during mild DKA. Materials and Methods We investigated nine patients with type 1 diabetes twice during: (i) euglycemic control conditions and a bolus of saline; and (ii) hyperglycemic ketotic conditions induced by lipopolysaccharide administration combined with insulin deprivation. Blood samples, indirect calorimetry, palmitate tracer and adipose tissue biopsies were used to investigate lipid metabolism. Results We observed a significant increase in plasma sCD163 levels after lipopolysaccharide exposure (P 

  • macrophage markers are poorly associated with liver histology in children with nonalcoholic fatty liver disease
    Journal of Pediatric Gastroenterology and Nutrition, 2018
    Co-Authors: Konstantin Kazankov, Anna Alisi, Holger Jon Moller, Rita De Vito, Soren Rittig, Birgitte Mahler, Valerio Nobili, Henning Gronbaek
    Abstract:

    OBJECTIVES We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P < 0.001). In the cross-sectional cohort, sCD163 only showed trends toward association with ballooning (rho = 0.14, P = 0.08) and portal inflammation (rho = 0.17, P = 0.08). sMR showed similar associations with liver histology. In the VSL#3 cohort, sCD163 correlated inversely with steatosis (rho = -0.35, P = 0.04), and lobular (rho = -0.57, P < 0.001) and portal inflammation (rho = -0.38, P = 0.02); sMR was not associated with any histological scores. Neither sCD163 nor sMR changed significantly during intervention, and without association with NAFLD resolution. CONCLUSIONS The macrophage activation markers sCD163 and sMR showed poor associations with liver histology in 2 different cohorts of children with biopsy-proven NAFLD, and none of the markers decreased during successful intervention. These results are in contrast with studies of adult NAFLD and may suggest a possibility of different roles for macrophages in the pathogenesis of adult and pediatric NAFLD.

  • Macrophage Markers Are Poorly Associated With Liver Histology in Children With Nonalcoholic Fatty Liver Disease.
    Journal of Pediatric Gastroenterology and Nutrition, 2018
    Co-Authors: Konstantin Kazankov, Anna Alisi, Holger Jon Moller, Rita De Vito, Soren Rittig, Birgitte Mahler, Valerio Nobili, Henning Gronbaek
    Abstract:

    OBJECTIVES We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P 

  • No effect of rifaximin on soluble CD163, mannose receptor or type III and IV neoepitope collagen markers in decompensated cirrhosis: Results from a randomized, placebo controlled trial
    2018
    Co-Authors: Nina Kimer, Holger Jon Moller, Natasja Stæhr Gudmann, Julie Steen Pedersen, Søren Møller, Mette Juul Nielsen, Diana Julie Leeming, Morten Asser Karsdal, Flemming Bendtsen, Henning Gronbaek
    Abstract:

    Background and aimsMacrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by systemic inflammation induced by bacterial translocation. Therefore, we aimed to investigate the effect of rifaximin-α, an antibiotic with effect on gut bacteria, on sCD163, sMR, and collagen metabolites.MethodsFifty-four clinically stable patients with decompensated cirrhosis were randomized to 4 weeks treatment with rifaximin-α (n = 36) or placebo (n = 18). Macrophage markers sCD163, sMR and markers of collagen fibrogenesis (C3M and C4M) and formation (PRO-C3 and P4NPS7) were analysed in plasma before and after treatment.ResultssCD163 and sMR levels were associated with liver disease severity (MELD score, sCD163 rho = 0.47, p 5.9 μg/ml, 38 patients) there was no effect of rifaximin-α on sCD163 (p = 0.49) or sMR levels (p = 0.32).ConclusionWe confirmed that macrophage activation markers sCD163 and sMR are directly associated to liver disease severity (MELD score). However, rifaximin-α has no effect on sCD163, sMR or collagen markers in decompensated cirrhosis and does therefore not seem to interfere with macrophage activation or fibrogenesis.

  • High hepatic macrophage activation and low liver function in stable Wilson patients - a Danish cross-sectional study
    BMC, 2018
    Co-Authors: Jessica Björklund, Holger Jon Moller, Hendrik Vilstrup, Thomas Damgaard Sandahl, Tea Lund Laursen, Peter Ott, Henning Gronbaek
    Abstract:

    Abstract Background Hepatic macrophage (Kupffer cell) hyperplasia is often described in Wilson’s disease (WD). In many liver diseases, Kupffer cell activation is related to disease severity, liver function, and fibrosis but the importance in WD is unknown. Kupffer cell activation can be assessed by the P-concentration of soluble (s)CD163, metabolic liver function by the galactose elimination capacity (GEC), and fibrosis by Fibroscan. We investigated the associations between sCD163, selected inflammatory cytokines, GEC, and liver fibrosis in Danish WD patients. Methods In a cross-sectional design, we studied 29 stable and well-treated patients (male/female15/14) with a median age of 35 years (IQR 24–50). P-sCD163 and cytokines were measured by ELISA. The GEC was measured by intra-venous galactose loading. Results The median P-sCD163 value at 2.96 mg/L (1.97–3.93) was high in the normal range (0.7–3.9) and seven patients (24%) had a value above the upper normal value. sCD163 correlated with TNF-α, IL-6 and IL-8 (rho> 0.50, p