title: Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice.
abstract: IL-1β is a cytokine critical to several inflammatory diseases in which pathogenic Th17 responses are implicated. Activation of the NLRP3 inflammasome by microbial and environmental stimuli can enable the caspase-1-dependent processing and secretion of IL-1β. The acute-phase protein serum amyloid A (SAA) is highly induced during inflammatory responses, wherein it participates in systemic modulation of innate and adaptive immune responses. Elevated levels of IL-1β, SAA, and IL-17 are present in subjects with severe allergic asthma, yet the mechanistic relationship among these mediators has yet to be identified. In this study, we demonstrate that Saa3 is expressed in the lungs of mice exposed to several mixed Th2/Th17-polarizing allergic sensitization regimens. SAA instillation into the lungs elicits robust TLR2-, MyD88-, and IL-1-dependent pulmonary neutrophilic inflammation. Furthermore, SAA drives production of IL-1α, IL-1β, IL-6, IL-23, and PGE(2), causes dendritic cell (DC) maturation, and requires TLR2, MyD88, and the NLRP3 inflammasome for secretion of IL-1β by DCs and macrophages. CD4(+) T cells polyclonally stimulated in the presence of conditioned media from SAA-exposed DCs produced IL-17, and the capacity of polyclonally stimulated splenocytes to secrete IL-17 is dependent upon IL-1, TLR2, and the NLRP3 inflammasome. Additionally, in a model of allergic airway inflammation, administration of SAA to the lungs functions as an adjuvant to sensitize mice to inhaled OVA, resulting in leukocyte influx after Ag challenge and a predominance of IL-17 production from restimulated splenocytes that is dependent upon IL-1R signaling.
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.forename: Karina
authors.initials: K
authors.lastname: Ckless
authors.forename: Rebecca
authors.initials: R
authors.lastname: Martin
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Foley
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Suratt
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Boyson
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
mesh_terms: D000485:Allergens / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000685:Serum Amyloid A Protein / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D000485:Allergens; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2