title: IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.
  
  
  METHODS
  The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.
  
  
  RESULTS
  We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis.
  
  
  CONCLUSIONS
  Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.
authors.affiliation: University of Orleans and CNRS, UMR6218, Orleans, France.
authors.forename: Paméla
authors.initials: P
authors.lastname: Gasse
authors.forename: Nicolas
authors.initials: N
authors.lastname: Riteau
authors.forename: Rachel
authors.initials: R
authors.lastname: Vacher
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Michel
authors.forename: Alain
authors.initials: A
authors.lastname: Fautrel
authors.forename: Franco
authors.initials: F
authors.lastname: di Padova
authors.forename: Lizette
authors.initials: L
authors.lastname: Fick
authors.forename: Sabine
authors.initials: S
authors.lastname: Charron
authors.forename: Vincent
authors.initials: V
authors.lastname: Lagente
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: François
authors.initials: F
authors.lastname: Huaux
authors.forename: Maria
authors.initials: M
authors.lastname: Leite-de-Moraes
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D053773:Transforming Growth Factor beta1; D001761:Bleomycin