Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation

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  • Elin Silverpil
    Lung Immunology Group, Department of Internal Medicine and Clinical Nutrition/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Adam KA Wright
    Biomedical Research Centre in Microbial Diseases, National institute of Health Research, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
  • Marit Hansson
    Lung Immunology Group, Department of Internal Medicine and Clinical Nutrition/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Pernilla Jirholt
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Louise Henningsson
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Margaretha E Smith
    Lung Immunology Group, Department of Internal Medicine and Clinical Nutrition/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Stephen B Gordon
    Respiratory Infection Group, Liverpool School of Tropical Medicine, Liverpool, UK
  • Yoichiro Iwakura
    Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, and Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
  • Inger Gjertsson
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Pernilla Glader
    Lung Immunology Group, Department of Internal Medicine and Clinical Nutrition/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Anders Lindén
    Unit for Lung and Airway Research, Physiology Division, Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

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説明

<jats:p> It is now established that IL-17 has a broad pro-inflammatory potential in mammalian host defense, in inflammatory disease and in autoimmunity, whereas little is known about its anti-inflammatory potential and inhibitory feedback mechanisms. Here, we examined whether IL-17A can inhibit the extracellular release of IL-23 protein, the upstream regulator of IL-17A producing lymphocyte subsets, that is released from macrophages during pulmonary inflammation. We characterized the effect of IL-17A on IL-23 release in several models of pulmonary inflammation, evaluated the presence of IL-17 receptor A (RA) and C (RC) on human alveolar macrophages and assessed the role of the Rho family GTPase Rac1 as a mediator of the effect of IL-17A on the release of IL-23 protein. In a model of sepsis-induced pneumonia, intravenous exposure to Staphylococcus aureus caused higher IL-23 protein concentrations in cell-free bronchoalveolar lavage (BAL) samples from IL-17A knockout (KO) mice, compared with wild type (WT) control mice. In a model of Gram-negative airway infection, pre-treatment with a neutralizing anti-IL-17A Ab and subsequent intranasal (i.n.) exposure to LPS caused higher IL-23 and IL-17A protein concentrations in BAL samples compared with mice exposed to LPS, but pre-treated with an isotype control Ab. Moreover, i.n. exposure with IL-17A protein per se decreased IL- 23 protein concentrations in BAL samples. We detected IL-17RA and IL-17RC on human alveolar macrophages, and found that in vitro stimulation of these cells with IL-17A protein, after exposure to LPS, decreased IL-23 protein in conditioned medium, but not IL-23 p19 or p40 mRNA. This study indicates that IL-17A can partially inhibit the release of IL-23 protein during pulmonary inflammation, presumably by stimulating the here demonstrated receptor units IL-17RA and IL-17RC on alveolar macrophages. Hypothetically, the demonstrated mechanism may serve as negative feedback to protect from excessive IL-17A signaling and to control antibacterial host defense once it is activated. </jats:p>

収録刊行物

  • Innate Immunity

    Innate Immunity 19 (5), 479-492, 2013-01-07

    SAGE Publications

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