Inflammatory Resolution Triggers a Prolonged Phase of Immune Suppression through COX-1/mPGES-1-Derived Prostaglandin E

Autor: 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
Rok vydání: 2017
Předmět:
Zdroj: Cell Reports
ISSN: 2211-1247
Popis: Summary 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.
Graphical Abstract
Highlights • Inflammatory resolution triggers T/NK cell infiltration, which synthesizes IFNγ • Through IP-10, IFNγ indirectly triggers monocyte-derived macrophage infiltration • Macrophages are directly acted upon by IFNγ to make abundant PGE2 • PGE2 exerts a phase of post-inflammation immune suppression and tolerance
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.
Databáze: OpenAIRE
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