title: NLRP3/caspase-1-independent IL-1beta production mediates diesel exhaust particle-induced pulmonary inflammation.
abstract: Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung; however, the mechanisms are largely unclear. IL-1β/IL-1RI signaling is crucial in several lung inflammatory responses. Typically, caspase-1 is activated within the NLRP3 inflammasome that recognizes several damage-associated molecular patterns, which results in cleavage of pro-IL-1β into mature IL-1β. In this study, we hypothesized that the NLRP3/caspase-1/IL-1β pathway is critical in DEP-induced lung inflammation. Upon DEP exposure, IL-1RI knockout mice had reduced pulmonary inflammation compared with wild-type mice. Similarly, treatment with rIL-1R antagonist (anakinra) and IL-1β neutralization impaired the DEP-induced lung inflammatory response. Upon DEP exposure, NLRP3 and caspase-1 knockout mice, however, showed similar IL-1β levels and comparable pulmonary inflammation compared with wild-type mice. In conclusion, these data show that the DEP-induced pulmonary inflammation acts through the IL-1β/IL-1RI axis. In addition, DEP initiates inflammation independent of the classical NLRP3/caspase-1 pathway, suggesting that other proteases might be involved.
authors.affiliation: Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, 9000 Ghent, Belgium. sharen.provoost@UGent.be
authors.forename: Sharen
authors.initials: S
authors.lastname: Provoost
authors.forename: Tania
authors.initials: T
authors.lastname: Maes
authors.forename: Nele S
authors.initials: NS
authors.lastname: Pauwels
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Tournoy
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D001335:Vehicle Emissions; D020170:Caspase 1