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Low Interleukin-22 Binding Protein Is Associated with High Mortality In ARTICLE 1 Low Interleukin-22 Binding Protein Is Associated With High Mortality in Alcoholic Hepatitis and Modulates LIVER Interleukin-22 Receptor Expression 08/26/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3PE2KhmxLsUKwRUb9LEtaRQ9wXW4bkT7EyguzqSnjJYw= by https://journals.lww.com/ctg from Downloaded Sidsel Støy, MD, PhD1, Tea Lund Laursen, MD1, Emilie Glavind, MD, PhD1, Peter Lykke Eriksen, MD, PhD1, Ewa Terczynska-Dyla, PhD2, Downloaded Nils Erik Magnusson, PhD3, Stephen Hamilton-Dutoit, MD, PhD4, Frank Viborg Mortensen, MD, PhD5, Sanne Skovgård Veidal, PhD6, Kristoffer Rigbolt, PhD6, Oliviero Riggio, MD, PhD7, Bent Deleuran, MD, DMSc8, Hendrik Vilstrup, MD, DSc1 and from Thomas Damgaard. Sandahl, MD, PhD1 https://journals.lww.com/ctg INTRODUCTION: In alcoholic hepatitis (AH), high interleukin (IL)-22 production is associated with disease improvement, purportedly through enhanced infection resistance and liver regeneration. IL-22 binding protein (BP) by binds and antagonizes IL-22 bioactivity, but data on IL-22BP in liver disease suggest a complex BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3PE2KhmxLsUKwRUb9LEtaRQ9wXW4bkT7EyguzqSnjJYw= interplay. Despite the scarcity of human data, IL-22 is in clinical trial as treatment of AH. We, therefore, in patients with AH, described the IL-22 system focusing on IL-22BP and associations with disease course, and mechanistically pursued the human associations in vitro. METHODS: We prospectively studied 41 consecutive patients with AH at diagnosis, days 7 and 90, and followed them for up to 1 year. We measured IL-22 pathway proteins in liver biopsies and blood and investigated IL-22BP effects on IL-22 in hepatocyte cultures. RESULTS: IL-22BP was produced in the gut and was identifiable in the patients with AH’ livers. Plasma IL-22BP was only 50% of controls and the IL-22/IL-22BP ratio thus elevated. Consistently, IL-22-inducible genes were upregulated in AH livers at diagnosis. Low plasma IL-22BP was closely associated with high 1-year mortality. In vitro, IL-22 stimulation reduced IL-22 receptor (R) expression, but coincubation with IL-22BP sustained IL-22R expression. In the AH livers, IL-22R mRNA expression was similar to healthy livers, although IL-22R liver protein was higher at diagnosis. DISCUSSION: Plasma IL-22BP was associated with an adverse disease course, possibly because its low level reduces IL-22R expression so that IL-22 bioactivity was reduced. This suggests the IL-BP interplay to be central in AH pathogenesis, and in future treatment trials (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/CTG/A338). SUPPLEMENTARY MATERIAL accompanies this paper at https://links.lww.com/CTG/A325, https://links.lww.com/CTG/A326, https://links.lww.com/CTG/A327, on https://links.lww.com/CTG/A328, https://links.lww.com/CTG/A338 08/26/2020 Clinical and Translational Gastroenterology 2020;11:e00197. https://doi.org/10.14309/ctg.0000000000000197 INTRODUCTION The bioactivity of IL-22 is regulated by its binding protein (BP) Alcoholic hepatitis (AH) carries a high mortality (1). The current, IL-22BP, which has an off-rate 1,0003 that of the surface bound but controversial treatment with corticosteroids, has uncertain receptor (5). Production of IL-22BP is detected in dendritic cells, effects on survival, but increases the risk of infections (2–4). New eosinophils, and T cells in the gut and can be inhibited by com- treatment strategies are urgently needed, and interleukin (IL)-22 ponents of the inflammasome, which is highly activated in AH is a promising candidate. (6–9). IL-22BP is proposed to act as a rheostat to tightly regulate 1Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; 3Diabetes and Hormone Diseases-Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Denmark; 4Department of Pathology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; 6Gubra, Hørsholm, Denmark; 7Department of Clinical Medicine, Sapienza University of Rome, Italy; 8Department of Biomedicine, Aarhus University, Aarhus, Denmark. Correspondence: Sidsel Støy, MD. E-mail: [email protected]. Received December 22, 2019; accepted June 12, 2020; published online August 19, 2020 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology American College of Gastroenterology Clinical and Translational Gastroenterology 2 Støy et al. IL-22 functions (10). However, data on the role of IL-22BP in liver cirrhosis (n 5 15) from the department’s biobank. In addition, diseases are few and conflicting. Gene variants of IL-22BP asso- patients with nonalcoholic fatty liver (n 5 12) and non- ciated with high IL-22BP expression are related to the de- alcoholic steatohepatitis (n 5 13) were included (20). More- velopment of severe fibrosis in schistosomiasis and hepatitis C, over, a cohort of patients with cirrhosis (n 5 29) undergoing whereas IL-22BP knock-out mice are more susceptible to acute transjugular intrahepatic portosystemic shunt was acquired liver injury (11,12). from Sapienza University of Rome for comparison of periph- Regarding AH, a high number of IL-22-producing T cells is eral vein and portal vein plasma. Healthy liver tissue for RNA LIVER associated with disease improvement, which may be related to sequencing was obtained from the healthy rim of liver resec- both improved resistance to infection and repair of the liver tates during operations for metastatic colon cancer at the (13,14). Based on animal studies, the effects are proposed to be Department of Abdominal Surgery, Aarhus University Hos- IL-22-dependent production of antimicrobial peptides such as pital, and for immunohistochemistry, from the pathologist lipocalin-2 and mitogenic and antiapoptotic gene induction biobank at Aarhus University Hospital. Written informed (15–18). Whether these are also the mechanisms of action of IL- consent was obtained before inclusion in the study, and the 22 in human beings and particularly in AH has not been study was conducted in accordance with the Helsinki decla- explored. ration. The study was approved by the Central Denmark Re- IL-22 signals via its surface-bound IL-22 receptor (R)-IL10R2 gion Ethical Committee (j.no. 1-10-72-40-13) and the Danish complex, which is almost exclusively expressed on epithelial- Data Protection Agency and registered at clinicaltrials.gov derived cells such as hepatocytes (17). This activates the signal (NCT01918462). transducer and activator of transcription (STAT)3 and its in- hibitor suppressor of cytokine signaling (SOCS)3 (19). Given this background, we conducted a series of human and in ELISA of IL-22, IL-22BP, and lipocalin-2 vitro experiments: the former to describe the components of the Commercially available ELISA kits (IL-22 [ThermoFisher Sci- fi IL-22 system and associations to clinical outcomes and the latter enti c], IL-22BP [Raybio, Norcross], and lipocalin-2 [R&D, fl to mechanistically explore the human findings. We hypothesized Abingdon, UK] were tested and optimized to avoid the in uence that low IL-22BP and high IL-22 were associated with a favorable of heterophilic antibodies (21). Spiking the IL-22 and IL-22BP outcome, that IL-22 pathway proteins were induced and that IL- ELISAs with recombinant IL-22BP and IL-22, respectively, did 22BP would block IL-22 mediated effects. not change the measured protein concentration, suggesting that we were in fact measuring total IL-22 and IL-22BP. We therefore METHODS report the calculated IL-22/IL-22BP ratio as a measure of free Study design and population IL-22. In this prospective cohort study, the patients with AH were di- agnosed at and consecutively recruited from the Department of Histology and immunohistochemistry Hepatology and Gastroenterology, Aarhus University Hospital, Liver biopsies (n 5 25) were scored by an experienced liver pa- Denmark between March 2013 and December 2017. Diagnosis thologist according to the Alcoholic Hepatitis Histologic Score was based on the following criteria: a history of excessive alcohol . (22). Immunohistochemistry was performed using the fully au- consumption for men 50 g/d and women 40 g/d (mean intake tomated VENTANA BenchMark ULTRA staining system men: 120 g/d [SD 60] and women: 121 g/d [SD 82]) with a period (Ventana Medical Systems, Tucson, AZ) with antigen retrieval at of abstinence of less than 4 weeks leading up to disease pre- high pH using ULTRA Cell Conditioning (Ventana Medical sentation, acute jaundice with presentation within the previous 2 . m Systems). Incubation was performed with optimized concentra- weeks and with serum bilirubin 80 mol/L, and age between 18 tions of the following antibodies IL-22BP (Clone #214518, R&D and 75 years. Liver biopsy was performed in 25 cases (see Sup- Systems, Minneapolis, MN, 1:500), IL-22R (HPA042399, Sigma- plementary Digital Content 1, http://links.lww.com/CTG/A325). Aldrich, St. Louis, MO, 1:500), and lipocalin-2 (HPA002695, Exclusion criteria were other underlying liver disease, hepato- Sigma-Aldrich, 1:200) for 32 minutes, followed by peroxidase cellular carcinoma, gallstones, uncontrolled infection, upper staining and detection with Optiview DAB (Ventana Medical gastrointestinal bleeding, or immunomodulatory therapy within Systems). A range of IL-22 antibodies were tested without suc-
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