PMID- 33776793 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220421 IS - 1664-042X (Print) IS - 1664-042X (Electronic) IS - 1664-042X (Linking) VI - 12 DP - 2021 TI - Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity. PG - 632502 LID - 10.3389/fphys.2021.632502 [doi] LID - 632502 AB - BACKGROUND AND AIMS: Immunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and in vitro neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear. METHODS: In Alcoholic Hepatitis (AH; n = 19), alcohol-related cirrhosis (ARC; n = 53) and healthy control (HC; n = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-blood soluble-CR expression upon bacterial challenge. By FACS, we assessed the relationship between soluble-TIM3 and membrane-TIM3 and rescue of immunity in bacterial-challenged PBMCs. RESULTS: Soluble-TIM3 was the dominant plasma soluble-CR in ALD vs. HC (p = 0.00002) and multivariate analysis identified it as the main driver of differences between groups. Soluble-CRs were strongly correlated with pro-inflammatory cytokines, gut bacterial translocation markers and clinical indices of disease severity. Ethanol exposure or bacterial challenge did not induce soluble-TIM3 production from PCLS nor from whole-blood. Bacterial challenge prompted membrane-TIM3 hyperexpression on PBMCs from ALD patient's vs. HC (p < 0.002) and was inversely correlated with plasma soluble-TIM3 levels in matched patients. TIM3 ligands soluble-Galectin-9 and soluble-CEACAM1 were elevated in ALD plasma (AH > ARC; p < 0.002). In vitro neutralization of Galectin-9 and soluble-CEACAM1 improved the defective anti-bacterial and anti-inflammatory cytokine production from E. coli-challenged PBMCs in ALD patients. CONCLUSIONS: Alcohol-related liver disease patients exhibit supra-physiological plasma levels of soluble-TIM3, particularly those with greater disease severity. This is also associated with increased levels of soluble TIM3-ligands and membrane-TIM3 expression on immune cells. Soluble-TIM3 can block the TIM3-ligand synapse and improve anti-bacterial immunity; however, the increased levels of soluble TIM3-binding ligands in patients with ALD negate any potential immunostimulatory effects. We believe that anti-TIM3 neutralizing antibodies currently in Phase I clinical trials or soluble-TIM3 should be investigated further for their ability to enhance anti-bacterial immunity. These agents could potentially represent an innovative immune-based supportive approach to rescue anti-bacterial defenses in ALD patients. CI - Copyright (c) 2021 Riva, Palma, Devshi, Corrigall, Adams, Heaton, Menon, Preziosi, Zamalloa, Miquel, Ryan, Wright, Fairclough, Evans, Shawcross, Schierwagen, Klein, Uschner, Praktiknjo, Katzarov, Hadzhiolova, Pavlova, Simonova, Trebicka, Williams and Chokshi. FAU - Riva, Antonio AU - Riva A AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. FAU - Palma, Elena AU - Palma E AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. FAU - Devshi, Dhruti AU - Devshi D AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. FAU - Corrigall, Douglas AU - Corrigall D AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. AD - Department of Gastroenterology, Basildon University Hospital, Basildon, United Kingdom. FAU - Adams, Huyen AU - Adams H AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. AD - Department of Gastroenterology, Royal Berkshire Hospital, Reading, United Kingdom. FAU - Heaton, Nigel AU - Heaton N AD - Institute of Liver Studies, King's College London, London, United Kingdom. FAU - Menon, Krishna AU - Menon K AD - Institute of Liver Studies, King's College London, London, United Kingdom. FAU - Preziosi, Melissa AU - Preziosi M AD - Institute of Liver Studies, King's College London, London, United Kingdom. FAU - Zamalloa, Ane AU - Zamalloa A AD - Institute of Liver Studies, King's College London, London, United Kingdom. FAU - Miquel, Rosa AU - Miquel R AD - Liver Histopathology Laboratory, Institute of Liver Studies, King's College Hospital, London, United Kingdom. FAU - Ryan, Jennifer M AU - Ryan JM AD - Gastrointestinal and Liver Services, Royal Free Hospital, London, United Kingdom. FAU - Wright, Gavin AU - Wright G AD - Department of Gastroenterology, Basildon University Hospital, Basildon, United Kingdom. FAU - Fairclough, Sarah AU - Fairclough S AD - Department of Gastroenterology, Basildon University Hospital, Basildon, United Kingdom. FAU - Evans, Alexander AU - Evans A AD - Department of Gastroenterology, Royal Berkshire Hospital, Reading, United Kingdom. FAU - Shawcross, Debbie AU - Shawcross D AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. FAU - Schierwagen, Robert AU - Schierwagen R AD - Translational Hepatology, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. FAU - Klein, Sabine AU - Klein S AD - Translational Hepatology, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. FAU - Uschner, Frank E AU - Uschner FE AD - Translational Hepatology, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. FAU - Praktiknjo, Michael AU - Praktiknjo M AD - Department of Internal Medicine I, University of Bonn, Bonn, Germany. FAU - Katzarov, Krum AU - Katzarov K AD - Department of Gastroenterology, Hepatobiliary Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria. FAU - Hadzhiolova, Tanya AU - Hadzhiolova T AD - Department of Gastroenterology, Hepatobiliary Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria. FAU - Pavlova, Slava AU - Pavlova S AD - Department of Gastroenterology, Hepatobiliary Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria. FAU - Simonova, Marieta AU - Simonova M AD - Department of Gastroenterology, Hepatobiliary Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria. FAU - Trebicka, Jonel AU - Trebicka J AD - Translational Hepatology, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. AD - European Foundation for the Study of Chronic Liver Failure (EF-CLIF), Barcelona, Spain. FAU - Williams, Roger AU - Williams R AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. FAU - Chokshi, Shilpa AU - Chokshi S AD - Institute of Hepatology, Foundation for Liver Research, London, United Kingdom. AD - Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. LA - eng PT - Journal Article DEP - 20210310 PL - Switzerland TA - Front Physiol JT - Frontiers in physiology JID - 101549006 PMC - PMC7987668 OTO - NOTNLM OT - TIM3 OT - alcohol OT - alcohol-related liver disease OT - biomarker OT - immune checkpoint COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/03/30 06:00 MHDA- 2021/03/30 06:01 PMCR- 2021/03/10 CRDT- 2021/03/29 06:23 PHST- 2020/11/23 00:00 [received] PHST- 2021/02/10 00:00 [accepted] PHST- 2021/03/29 06:23 [entrez] PHST- 2021/03/30 06:00 [pubmed] PHST- 2021/03/30 06:01 [medline] PHST- 2021/03/10 00:00 [pmc-release] AID - 10.3389/fphys.2021.632502 [doi] PST - epublish SO - Front Physiol. 2021 Mar 10;12:632502. doi: 10.3389/fphys.2021.632502. eCollection 2021.