Macrophage markers and innate immunity in cirrhosis

We read with great interest the review article "Innate immune cells in cirrhosis" by Bernsmeier et al.[1]Bernsmeier C. van der Merwe S. Périanin A. Innate immune cells in cirrhosis.J Hepatol. 2020; 73: 186-201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar We strongly agree on the important role of innate immune cells, especially monocytes and macrophages viz. Kupffer cells, in the development and progression of liver cirrhosis and complications such as acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Even though the review is very comprehensive, we think it is missing a section on macrophage biomarkers to further support the role of macrophages in cirrhosis development and progression including complications.[2]Nielsen M.C. Hvidbjerg Gantzel R. Clària J. Trebicka J. Møller H.J. Grønbæk H. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure.Cells. 2020; 9: 1175Crossref Scopus (33) Google Scholar The most thoroughly studied biomarker is soluble (s)CD163, which originates exclusively from monocytes and macrophages; during macrophage activation, it is shed from the cell surface by the TACE/ADAM enzyme, which also cleaves pro-TNFα.[2]Nielsen M.C. Hvidbjerg Gantzel R. Clària J. Trebicka J. Møller H.J. Grønbæk H. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure.Cells. 2020; 9: 1175Crossref Scopus (33) Google Scholar The macrophage activation marker soluble mannose receptor (sMR), also detected on dendritic and endothelial cells, is most likely shed by proteolytic activity.[2]Nielsen M.C. Hvidbjerg Gantzel R. Clària J. Trebicka J. Møller H.J. Grønbæk H. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure.Cells. 2020; 9: 1175Crossref Scopus (33) Google Scholar The soluble urokinase plasminogen activator receptor (suPAR) is ubiquitously expressed on immune cells, including neutrophils, lymphocytes, monocytes and macrophages, and is cleaved by proteases upon inflammation. Other biomarkers may include cytokines and microRNAs; the latter possess diagnostic and prognostic relevance in NAFLD-related fibrosis.[3]Lin H.Y. Yang Y.L. Wang P.W. Wang F.S. Huang Y.H. The emerging role of microRNAs in NAFLD: highlight of microRNA-29a in modulating oxidative stress, inflammation, and beyond.Cells. 2020; 9: 1041Crossref Scopus (25) Google Scholar In recent years, sCD163, sMR and suPAR have been investigated in acute and chronic inflammatory liver diseases. As shown in Fig. 1A and 1C, there is a stepwise increase in sCD163 and sMR levels in parallel with worsening inflammation and fibrosis in NAFLD, chronic HBV and HCV,[4]Kazankov K. Barrera F. Møller H.J. Bibby B.M. Vilstrup H. George J. et al.Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C.Hepatology. 2014; 60: 521-530Crossref PubMed Scopus (113) Google Scholar alcohol-related liver disease, primary biliary cholangitis and Wilson Disease; the lowest levels are seen in patients with NAFLD without fibrosis, and the highest in cirrhosis of different etiologies. Both markers show a concentration-gradient across the liver suggesting intrahepatic excretion.[5]Holland-Fischer P. Gronbaek H. Sandahl T.D. Moestrup S.K. Riggio O. Ridola L. et al.Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS.Gut. 2011; 60: 1389-1393Crossref PubMed Scopus (94) Google Scholar A few studies demonstrated increasing suPAR levels with incrementing degrees of inflammation and fibrosis in patients with NAFLD, HBV and HCV. In patients with established cirrhosis, sCD163, sMR and suPAR significantly associate with liver disease severity, e.g. MELD and Child-Pugh scores, as well as the degree of portal hypertension5Holland-Fischer P. Gronbaek H. Sandahl T.D. Moestrup S.K. Riggio O. Ridola L. et al.Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS.Gut. 2011; 60: 1389-1393Crossref PubMed Scopus (94) Google Scholar, 6Zimmermann H.W. Koch A. Seidler S. Trautwein C. Tacke F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis.Liver Int. 2012; 32: 500-509PubMed Google Scholar, 7Waidmann O. Brunner F. Herrmann E. Zeuzem S. Piiper A. Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis.J Hepatol. 2013; 58: 956-961Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar (Fig. 1B–D). Importantly, sCD163, sMR and suPAR also add prognostic information in cirrhosis in terms of decompensating events and mortality.[6]Zimmermann H.W. Koch A. Seidler S. Trautwein C. Tacke F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis.Liver Int. 2012; 32: 500-509PubMed Google Scholar Remarkably, sCD163 and sMR levels decrease during interventions ameliorating liver inflammation and fibrosis as demonstrated after antiviral treatment for patients with HBV and HCV, following life-style intervention or bariatric surgery in childhood and adult patients with NAFLD, and after steroid treatment in patients with autoimmune hepatitis. Interestingly, sCD163 and sMR levels are unaffected by lowering portal hypertension with a transjugular intrahepatic portosystemic shunt,[5]Holland-Fischer P. Gronbaek H. Sandahl T.D. Moestrup S.K. Riggio O. Ridola L. et al.Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS.Gut. 2011; 60: 1389-1393Crossref PubMed Scopus (94) Google Scholar suggesting constitutive activation of liver macrophages in cirrhosis. The highest overall sCD163, sMR and suPAR levels are found in patients with the most severe forms of liver diseases such as acute liver failure, alcoholic hepatitis, acute autoimmune hepatitis and ACLF.[2]Nielsen M.C. Hvidbjerg Gantzel R. Clària J. Trebicka J. Møller H.J. Grønbæk H. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure.Cells. 2020; 9: 1175Crossref Scopus (33) Google Scholar,[8]Gronbaek H. Rodgaard-Hansen S. Aagaard N.K. Arroyo V. Moestrup S.K. Garcia E. et al.Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF).J Hepatol. 2016; 64: 813-822Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar In ACLF, sCD163 and sMR are independently associated with severity and prognosis; the addition of sCD163 and sMR to standard clinical scores (CLIF-C ACLF and CLIF-C AD scores) improves the prognostic capability.[8]Gronbaek H. Rodgaard-Hansen S. Aagaard N.K. Arroyo V. Moestrup S.K. Garcia E. et al.Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF).J Hepatol. 2016; 64: 813-822Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Further, in ACLF, the combination of sCD163 and urinary neutrophil gelatinase-associated lipocalin further improved mortality prediction. Recently, sCD163 and sMR were linked to changes in metabolic pathways of mitochondrial energy production, contributing to the development of organ failure in ACLF.[9]Moreau R. Claria J. Aguilar F. Fenaille F. Lozano J.J. Junot C. et al.Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.J Hepatol. 2020; 72: 688-701Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Further, a broad panel of cytokines and chemokines, some excreted by macrophages, others potent stimulators of macrophage activation and monocyte migration, were evaluated in AD and ACLF. The highest numbers of elevated markers were found in ACLF, where the baseline cytokine and chemokine profiles among AD patients who developed ACLF were significantly elevated compared with AD patients who did not progress to ACLF. We suggest that constitutive upregulation of liver macrophage activation by cirrhosis and the underlying liver disease per se, as demonstrated by increased sCD163, sMR and suPAR levels, represent a vulnerable condition with a resulting exaggerated immune response caused by any precipitating event in AD/ACLF. This may offset a chain of severe hepatic and systemic inflammation accompanied by immune exhaustion, organ hypoperfusion, further liver dysfunction and subsequently multiorgan failure as suggested by Bernsmeier et al.[1]Bernsmeier C. van der Merwe S. Périanin A. Innate immune cells in cirrhosis.J Hepatol. 2020; 73: 186-201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Thus, the accumulating evidence from macrophage-specific biomarkers emphasizes the important role of the Kupffer cells and infiltrating monocytes in liver disease development and progression. We fully support the concept of specific immunomodulatory targeting in patients with cirrhosis, especially in ACLF,[1]Bernsmeier C. van der Merwe S. Périanin A. Innate immune cells in cirrhosis.J Hepatol. 2020; 73: 186-201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar and suggest that macrophage-specific molecules are used as companion biomarkers for such interventions. Interestingly, the CD163 receptor itself, in its cell-bound form, may constitute a promising entry-molecule for targeted delivery of drugs to Kupffer cells.[10]Graversen J.H. Moestrup S.K. Drug trafficking into macrophages via the endocytotic receptor CD163.Membranes. 2015; 5: 228-252Crossref PubMed Scopus (14) Google Scholar The authors received no financial support to produce this manuscript. HG idea and concept, drafted the letter, RGH compiled data for the figure, TLL, KK, and HJM intellectual input. All authors approved the final version of the manuscript. HG received research grants from Abbvie, Intercept, Arla, NOVO Nordisk Foundation; Advisory board Ipsen, and speaker Norgine. KK: speaker Norgine. RHG, TLL and HJM none. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.18 MB) Help with pdf files disclosures.pdf Innate immune cells in cirrhosisJournal of HepatologyVol. 73Issue 1PreviewCirrhosis is a multisystemic disease wherein inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to bacterial infections, which may precipitate acute decompensation and acute-on-chronic liver failure, both of which are associated with high short-term mortality. Innate immune cells are an essential first line of defence against pathogens. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes in the liver, and promote tissue damage. Full-Text PDF