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

Research output: Contribution to journalArticlepeer-review

Abstract

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. Inflammatory resolution was believed to lead affected tissues back to homeostasis. Newson et al. now find that resolution triggers a prolonged phase of localized immune suppression called “adapted homeostasis.” This phase is mediated by macrophage-derived prostaglandin E2 derived from COX-1/mPGES1 and is crucial in preventing the development of autoimmunity.

Original languageEnglish
Pages (from-to)3162-3175
Number of pages14
JournalCell Reports
Volume20
Issue number13
Early online date26 Sept 2017
DOIs
Publication statusPublished - 26 Sept 2017

Keywords

  • adaptive homeostasis
  • autoimmunity
  • eicosanoid
  • immune scarring
  • macrophage

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