Inflammatory Resolution Triggers a Prolonged Phase of Immune Suppression through COX-1/mPGES-1-Derived Prostaglandin E2
Justine Newson,
Madhur P. Motwani,
Alexandra C. Kendall,
Anna Nicolaou,
Giulio G. Muccioli,
Mireille Alhouayek,
Melanie Bennett,
Rachel Van De Merwe,
Sarah James,
Roel P.H. De Maeyer,
Derek W. Gilroy
Affiliations
Justine Newson
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Madhur P. Motwani
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Alexandra C. Kendall
Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
Anna Nicolaou
Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
Giulio G. Muccioli
Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Av. E. Mounier, 72 (B1.72.01), 1200 Bruxelles, Belgium
Mireille Alhouayek
Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Av. E. Mounier, 72 (B1.72.01), 1200 Bruxelles, Belgium
Melanie Bennett
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Rachel Van De Merwe
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Sarah James
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Roel P.H. De Maeyer
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Derek W. Gilroy
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK
Acute inflammation is characterized by granulocyte infiltration followed by efferocytosing mononuclear phagocytes, which pave the way for inflammatory resolution. Until now, it was believed that resolution then leads back to homeostasis, the physiological state tissues experience before inflammation occurred. However, we discovered that resolution triggered a prolonged phase of immune suppression mediated by prostanoids. Specifically, once inflammation was switched off, natural killer cells, secreting interferon γ (IFNγ), infiltrated the post-inflamed site. IFNγ upregulated microsomal prostaglandin E synthase-1 (mPGES-1) alongside cyclo-oxygenase (COX-1) within macrophage populations, resulting in sustained prostaglandin (PG)E2 biosynthesis. Whereas PGE2 suppressed local innate immunity to bacterial infection, it also inhibited lymphocyte function and generated myeloid-derived suppressor cells, the net effect of which was impaired uptake/presentation of exogenous antigens. Therefore, we have defined a sequence of post-resolution events that dampens the propensity to develop autoimmune responses to endogenous antigens at the cost of local tissue infection.
