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Macrophage Activation Markers, CD163 and CD206, in Acute-On-Chronic Liver Failure

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cells Review Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure Marlene Christina Nielsen 1 , Rasmus Hvidbjerg Gantzel 2 , Joan Clària 3,4 , Jonel Trebicka 3,5 , Holger Jon Møller 1 and Henning Grønbæk 2,* 1 Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus N, Denmark; [email protected] (M.C.N.); [email protected] (H.J.M.) 2 Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, Denmark; [email protected] 3 European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain; [email protected] (J.C.); [email protected] (J.T.) 4 Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain 5 Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, 60323 Frankfurt, Germany * Correspondence: [email protected]; Tel.: +45-21-67-92-81 Received: 1 April 2020; Accepted: 4 May 2020; Published: 9 May 2020 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. Keywords: macrophage; scavenger receptor; sCD163; sCD206; inflammation; chronic liver disease; acute decompensation of cirrhosis; liver cirrhosis, acute-on-chronic liver failure; ACLF 1. Introduction: Macrophages, Inflammatory Liver Diseases, and ACLF Macrophages play a significant role in acute and chronic inflammatory liver diseases being involved in both liver disease development and progression but also disease resolution. Liver cirrhosis is the cardinal endpoint of chronic inflammatory liver diseases where especially development of portal hypertension increases the risk of complications. Acute decompensation (AD) represents the classical complications in patients with liver cirrhosis e.g., variceal bleeding, ascites with hepatorenal syndrome, and hepatic encephalopathy, which has a significant impact on morbidity and mortality. Further, patients with liver cirrhosis, with or without AD, are at risk of progression to Acute-on-Chronic Liver Failure (ACLF) characterized by organ failures most often preceded or accompanied by an extreme inflammatory response and a poor survival [1,2]. A consensus definition of ACLF was introduced with the CANONIC-study conducted by the EASL Chronic Liver Failure Consortium including data from 1343 patients hospitalized in liver Cells 2020, 9, 1175; doi:10.3390/cells9051175 www.mdpi.com/journal/cells Cells 2019, 8, x FOR PEER REVIEW 2 of 18 Cells 2020A ,consensus9, 1175 definition of ACLF was introduced with the CANONIC-study conducted by2 of the 18 EASL Chronic Liver Failure Consortium including data from 1343 patients hospitalized in liver units unitsthroughout throughout Europe. Europe. Main Main characteristics characteristics of ACLF of ACLF comprise comprise the the following following criteria criteria [[1]1]:: (1)1) acuteacute decompensationdecompensation (rapid (rapid development development of large-volumeof large-volume ascites, ascites, hepatic hepatic encephalopathy, encephalopathy, variceal bleedingvariceal andbleeding/or bacterial and/or infection); bacterial infection) (2) organ failure; 2) organ (defined failure with (defined the Chronic with the Liver Chronic Failure Liver (CLIF)-SOFA-score; Failure (CLIF)- aSOFA modified-score; version a modified of the version sequential of the organ sequential failure org assessmentan failure (SOFA) assessment score (SOFA) including score liver, including kidney, cerebral,liver, kidney, circulatory, cerebral, respiratory circulatory, and respiratory/or coagulation and/or failure); coagulation (3) high failure) 28-day; mortality3) high 28 rate.-day mortality rate. ACLF has an annual incidence among patients with compensated cirrhosis on 20.1 per 1000 personsACLF has[3]. an The annual 28-day incidence and 90-day among mortality patients rates rangewith betweencompensated 22–77% cirrhosis and 41–79%, on 20.1 respectively, per 1000 andpersons dramatically [3]. The 28 increase-day and with 90- theday number mortalit ofy rates organ range failures between [1]. A 22 refined–77% andand simplified41–79%, respectively, prognostic tool,and dramatically the CLIF-C ACLF-score, increase with including the number age and of whiteorgan bloodfailures cell [1] count. A refined in addition and simplified to CLIF-organ-failure prognostic score,tool, the was CLIF later-C introduced ACLF-score, and including predict mortality age and white with higher blood accuracycell count than in addition CLIF-SOFA, to CLIF Model-organ for- End-stagefailure score, Liver was Disease later (MELD)introduced and and Child-Pugh-score predict mortality [4]. with higher accuracy than CLIF-SOFA, ModelOrgan-specific for End-stage and Liver systemic Disease inflammation (MELD) and are Child fundamental-Pugh-score events [4]. in the development and course of chronicOrgan liver-specific diseases and [5s,ystemic6] and macrophages inflammation play are anfundamental important role events for diseasein the development andand progression.course of chronic Soluble liver CD163 diseases and CD206 [5,6] are and promising macrophages biomarkers play toan reveal important and quantify role for activation disease ofdevelopment the resident and liver progression. macrophages Soluble (Kup CD163ffer cells) and [6 CD206], which are have promising gained biomarkers attention from to reveal a clinical and perspectivequantify activation especially of the during resident the last liver decade. macrophages (Kupffer cells) [6], which have gained attention fromNew a clinical aspects perspective of immunopathology especially during in ACLF the last are decade highly. relevant to support and extent current understandings.New aspects We of intendimmunopathol to reviewogy the in literature ACLF are on highly macrophage relevant activation to support as part andof exte thent immune current responseunderstandings. in liver diseases,We intend especially to review in the ACLF, literature with a on focus macrophage on the soluble activation forms as of part CD163 of the and immune CD206 asresponse biomarkers in liver for diseases, ACLF disease especially severity in ACLF, and prognosis with a focus (Figure on the1). soluble forms of CD163 and CD206 as biomarkers for ACLF disease severity and prognosis (Figure 1). Figure 1. Macrophage activation in patients with acute-on-chronic liver failure (ACLF). Hepatic Figure 1. Macrophage activation in patients with acute-on-chronic liver failure (ACLF). Hepatic or or extra-hepatic precipitating factors result in the release and production of PAMPs and DAMPs. extra-hepatic precipitating factors result in the release and production of PAMPs and DAMPs. This This leads to increased CD163 and CD206 expression in liver resident macrophages (Kupffer cells), leads to increased CD163 and CD206 expression in liver resident macrophages (Kupffer cells), along along with increased shedding of the receptors from the Kupffer cells. CD163 shedding is mediated with increased shedding of the receptors from the Kupffer cells. CD163 shedding is mediated through through TACE-cleavage [7] and EV-associated release [8], whereas CD206 shedding is mediated through TACE-cleavage [7] and EV-associated release [8], whereas CD206 shedding is mediated through proteolytic cleavage [9] and possibly EV-associated release (unpublished data). The relationship Cells 2020, 9, 1175 3 of 18 proteolytic cleavage [9] and possibly EV-associated release (unpublished data). The relationship between CD163 and CD206 proteolytic cleavage and EV-associated release is not fully elucidated. Plasma concentrations of soluble CD163 and CD206 correlates with the severity of ACLF and are promising prognostic biomarkers in AD and ACLF [6]. Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; DILI, drug-induced liver injury; TIPS, transjugular intrahepatic portosystemic shunt; DAMPs, damage-associated molecular patterns, PAMPs, pathogen-associated molecular patterns; TACE, tumor necrosis factor α converting enzyme; EV, extracellular vesicle; HC, healthy controls; ACLF, Acute-on-Chronic Liver Failure; gr., grade; AD, acute decompensation. * Precipitating factors as presented in [1,5]. 2. Macrophages Macrophages were first recognized for their role in host immunity and phagocytosis, followed by evidence of their importance in development, tissue homeostasis, metabolism, and tissue regeneration [10,11]. Macrophages display a wide range of membrane receptors which recognize both host-derived and foreign ligands. Activation of these receptors
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