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

Silverpil, E., Wright, A. K., Hansson, M., Jirholt, P., Henningsson, L., Smith, M. E., Gordon, Stephen ORCID: https://orcid.org/0000-0001-6576-1116, Iwakura, Y., Gjertsson, I., Glader, P. and Linden, A. (2013) 'Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation'. Innate Immunity, Vol 19, Issue 5, pp. 479-492.

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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 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.

Item Type: Article
Subjects: QU Biochemistry > Proteins. Amino Acids. Peptides > QU 55 Proteins
WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 202 Pneumonia (General or not elsewhere classified)
WF Respiratory System > Lungs > WF 600 Lungs
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 200 Leukocytes. Leukocyte disorders (General)
WH Hemic and Lymphatic Systems > Lymphatic System > WH 650 Reticuloendothelial system
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1177/1753425912470470
Depositing User: Lynn Roberts-Maloney
Date Deposited: 12 Mar 2015 11:37
Last Modified: 06 Feb 2018 13:09
URI: http://archive.lstmed.ac.uk/id/eprint/5006

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