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

Journal article
Authors Elin Silverpil
A. K. A. Wright
Marit Hansson
Pernilla Jirholt
Louise Henningsson
Margaretha E. Smith
S. B. Gordon
Y. Iwakura
Inger Gjertsson
Pernilla Glader
A. Linden
Published in Innate Immunity
Volume 19
Issue 5
Pages 479-492
ISSN 1753-4259
Publication year 2013
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 479-492
Language en
Links dx.doi.org/10.1177/1753425912470470
Keywords IL-17, IL-23, macrophages, neutrophils, airway inflammation, Rac1, bronchoalveolar lavage, host, HUMAN ALVEOLAR MACROPHAGES, FIBROSIS LUNG-DISEASE, DELTA T-CELLS, NEUTROPHIL RECRUITMENT, AUTOIMMUNE INFLAMMATION, TH17 CELLS, INTERLEUKIN-12 PRODUCTION, RHEUMATOID-ARTHRITIS, AIRWAY INFLAMMATION, CYTOKINE SECRETION
Subject categories Immunology in the medical area

Abstract

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 invitro 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.

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