title: Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation.
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.
authors.affiliation: 1Lung 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.
authors.forename: Elin
authors.initials: E
authors.lastname: Silverpil
authors.forename: Adam K A
authors.initials: AK
authors.lastname: Wright
authors.forename: Marit
authors.initials: M
authors.lastname: Hansson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Jirholt
authors.forename: Louise
authors.initials: L
authors.lastname: Henningsson
authors.forename: Margaretha E
authors.initials: ME
authors.lastname: Smith
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gordon
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Inger
authors.initials: I
authors.lastname: Gjertsson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Glader
authors.forename: Anders
authors.initials: A
authors.lastname: Lindén
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000187:drug effects; D020381:Interleukin-17 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000276:immunology*; D018123:Receptors, Interleukin / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D013203:Staphylococcal Infections / Q000150:complications / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; C109985:IL17RA protein, human; C448419:IL17RC protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D008070:Lipopolysaccharides; C107953:RAC1 protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D020830:rac1 GTP-Binding Protein
keywords: IL-17; IL-23; Rac1; airway inflammation; bronchoalveolar lavage; host defense; human; macrophages; mouse; neutrophils