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While resolution is believed to switch inflammation off and return the affected tissues back to homeostasis, we found that it triggers a prolonged phase of immune suppression. During resolution of acute inflammation (∼72h) CD4+ and CD8+ lymphocytes as well as natural killer (NK) cells migrated into tissues secreting IFNγ from day 6. IFNγ carried out two distinct functions: firstly, through IP-10, IFNγ indirectly triggered monocyte infiltration, which differentiated into macrophages (moMϕs). Secondly, moMϕs were directly acted upon by IFNγ to express microsomal prostaglandin E synthase-1 (mPGES-1) alongside cyclooxygenase (COX 1) resulting in sustained prostaglandin (PG)E2 synthesis peaking at day 14 and lasting for several weeks. PGE2 suppressed innate immune responses to bacterial infection opening a prolonged window of postresolution infectious opportunity within the host. At the same time, it also differentially modulated multiple aspect of the adaptive immune system including suppressing lymphocyte function whilst also generating myeloid-derived suppressor cells, the net effect of which was impaired uptake/presentation of exogenous antigens. Therefore, we have defined a novel sequence of post-resolution events starting with IFNγ and culminating in sustained PGE2, which we propose dampens the propensity to develop autoimmune responses to endogenous antigens at the cost of local tissue infection.

O154 PROSTAGLANDIN E2 MEDIATES IMMUNOSUPPRESSION IN ACUTELY DECOMPENSATED CIRRHOSIS A. O’Brien, J. Fullerton, G. Auld, S. James, J. Newson, E. Karra, K. Massey, W. Alazawi, A. Winstanley, C. Juan, R. Garcia-Marquez, A. Nicolaou, D. Gilroy. Hepatology, Medicine, University College London (UCL), London, University of Manchester, Manchester, Barts and The London Medical School, London, United Kingdom; Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain E-mail: rmhaajo@ucl.ac.uk Background and Aims: Liver cirrhosis is one of the top 10 causes of death globally. Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. Innate immune dysfunction is thought to underlie this vulnerability, however no unifying cause has been identified. Methods: Lipidomic analysis was performed on plasma from patients with acutely decompensated (AD) cirrhosis, stable cirrhosis, end-stage liver disease (ESLD) and healthy volunteers. Human monocyte-derived macrophages were incubated in media containing plasma from cirrhosis patients in the presence/absence of prostaglandin E2 (PGE2) modulators. Cytokine levels/bacterial killing were used as markers of immune competence. In-vivo bacterial challenge/survival experiments were performed on bile duct ligation and carbon tetrachloride liver-injury mouse models. Results: PGE2 was elevated in acutely decompensated patients at immunosuppressive levels. Plasma from AD and ESLD patients suppressed macrophage cytokine secretion and bacteria killing in a PGE2 receptor-dependent manner. This immunosuppressive effect persisted up to 24 weeks after initial sampling, but was absent in stable cirrhosis. Both mouse models demonstrated elevated PGE2, which when inhibited restored immune competence and survival following infection. Albumin binds PGE2 and we found the immunosuppressive effects of AD plasma were enhanced in patients with low albumin levels. Administering 20% Human Albumin Solution to AD patients reversed the immunosuppressive properties of their plasma. Conclusions: We demonstrate for the first time that elevated PGE2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients. We propose the use of albumin to raise levels above 30mg/dl to inhibit PGE2 and restore immune competence in these patients.

Though fish oils possess cardio-protective, anti-inflammatory, and anti-cancer properties, their molecular and biochemical mechanism of action is lacking. In this issue of Chemistry & Biology, Tjonahen and colleagues [1] identify a new metabolite of eicosapentanoic acid, resolvin E2, produced by 5-lipoxygenase.