Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation

Authors

  • Ourania Koltsida,

    1. Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Sergey Karamnov,

    1. Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Katerina Pyrillou,

    1. Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece
    2. Division of Pharmacology-Pharmacotechnology, Center for Basic Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
    Search for more papers by this author
  • Thad Vickery,

    1. Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • Aikaterini-Dimitra Chairakaki,

    1. Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece
    Search for more papers by this author
  • Constantin Tamvakopoulos,

    1. Division of Pharmacology-Pharmacotechnology, Center for Basic Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
    Search for more papers by this author
  • Paschalis Sideras,

    1. Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece
    Search for more papers by this author
  • Charles N. Serhan,

    1. Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • Evangelos Andreakos

    Corresponding author
    1. Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece
    • Tel: +30 210 6597338; Fax: +30 210 6597545

    Search for more papers by this author

Abstract

Although specialized pro-resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self-RNA, mobilizes the docosahexaenoic acid (DHA)-derived biosynthetic pathways that lead to the generation of D-series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA-derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA-derived SPMs including PD1 and accelerated the catabasis of Th2-mediated inflammation. D-series SPMs were critical for TLR7-mediated resolution of airway inflammation as this effect was lost in Alox15−/− mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D-series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.

Ancillary