We sought to establish the role of MERTK and determine its candidacy as an immunotherapeutic target to reverse immuneparesis in ACLF. Methods: Patients with ACLF (n=30), cirrhosis (CLD; n=8) and healthy controls (HC; n=14) were studied. Immunophenotyping and LPS-induced TNF/IL-6 production were assessed by flow cytometry. Plasma Gas-6 levels were measured by ELISA (Abnova). Immunohistochemistry and multispectral imaging was done on liver (n=6 each) and mesenteric lymph nodes (n=1 each)

from ACLF and CLD patients undergoing transplantation. Monocyte phenotype was assessed following migration across hepatic endothelial monolayers into collagen plugs (HC, n=4;ACLF, n=5). MERTK inhibitor UNC569 (Millipore) was used. Purified HC derived monocytes were conditioned with ACLF plasma (n=9 patients) for 16h prior to MERTK progestogen antagonist inhibition. Results: Compared to HC and CLD, there was a marked expansion of circulating MERTK positive monocytes (MERTK+) in ACLF (mean 5.9/3.5vs.26.5%,p<0.0001/p<0.001). Levels of the MERTK ligand Gas-6 were increased (633vs.3203pg/ml,p<0.01). MERTK+ monocytes in ACLF revealed an anti-inflammatory www.selleckchem.com/products/RO4929097.html (CD163high,CX3CR1low,HLA-DRlow), lymph node homing (CCR7high) phenotype. Pro-inflammatory responses to LPS

challenge (TNF(mean MFI):14664vs.5496,p=0.0014) were attenuated. Culture of monocytes in ACLF compared to HC plasma expanded the number of MERTK+, anti-inflammatory, LPS-tol-erant cells (82.6vs.42.0%,p=0.0021). Compared to CLD, multispectral analysis of ACLF tissue

revealed a MERTK+ infiltrate within hepatic sinusoids (33.8vs.105.3/10HPF,p<0.01) and subcaspular/medullary areas of mesenteric lymph nodes (23vs.309/10HPF). Following migration across the endothe-lium a significant increase in MERTK+ monocytes was detected in ACLF compared to HC (75.8%vs.63.3%,p=0.01). Remarkably, inhibition of MERTK signalling significantly increased HLA-DR expression (p=0.0225) and improved GPX6 LPS-induced TNF production (p=0.0078). Conclusions: We have identified the presence and marked expansion of a novel immunoregulatory monocyte/mφ subset that suppresses innate immune responses to microbial challenge in patients with ACLF. Thus, MERTK provides a promising immunotherapeutic target to reverse immune-paresis and susceptibility to infection in ACLF. Disclosures: William Bernal – Consulting: Vital Therapies Inc Michael A. Heneghan – Speaking and Teaching: Falk Nigel Heaton – Advisory Committees or Review Panels: Novartis, Roche; Speaking and Teaching: Astellas Mark R. Thursz – Advisory Committees or Review Panels: Gilead, BMS, Abbott Laboratories Julia Wendon – Consulting: Pulsion, Excalenz The following people have nothing to disclose: Christine Bernsmeier, Oltin T. Pop, Evangelos Triantafyllou, Chris J. Weston, Stuart M. Curbishley, Vishal C.