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Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2

Abstract

Liver disease is one of the leading causes of death worldwide1. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system2,3,4; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

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Figure 1: Elevated PGE2 in plasma of patients admitted to hospital with acute decompensation is immunosuppressive.
Figure 2: Plasma from patients with ESLD but not from those with stable cirrhosis demonstrates PGE2-mediated immunosuppression.
Figure 3: Inhibiting PGE2 restores bacterial killing and survival following bacterial infection in mouse models of liver injury.
Figure 4: PGE2-mediated immunosuppression by AD plasma is improved by albumin.

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Acknowledgements

We thank R. Mookerjee (Royal Free Hospital) for allowing use of samples from the DASIMAR study, N. Shah for collecting these samples and N. Davies for technical assistance. We also thank A. Healey for technical support and H. Antoniades for facilitating sample acquisition. E. coli and GBS clinical isolates were provided by V. Gant, University College London Hospitals. D.W.G. is a Wellcome Trust senior research fellow and support for work presented here was provided by the Wellcome Trust. Support was also provided by a grant from the National Institute of Health Research University College London Hospitals Biomedical Research Centre (A.J.O.).

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D.W.G. and A.J.O. conceived of the idea, and A.J.O. carried out the work. D.W.G. and A.J.O. cowrote the paper, and J.N.F. edited. J.N.F., G.S., J.N., S.J., E.K. and G.A. carried out biochemical assays, and W.A. (Royal London Hospitals), J.C. and R.G.-M. (both from ALFAE and MACHT clinical trials) supplied clinical samples. K.A.M. and A.N. carried out ESI/LC-MS/MS analysis, and A.W. carried out histological analysis.

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Correspondence to Derek W Gilroy.

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The authors declare no competing financial interests.

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O'Brien, A., Fullerton, J., Massey, K. et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 20, 518–523 (2014). https://doi.org/10.1038/nm.3516

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