title: ATP binding cassette transporter G1 deletion induces IL-17-dependent dysregulation of pulmonary adaptive immunity.
abstract: Mice with genetic deletion of the cholesterol transporter ATP binding cassette G1 (ABCG1) have pulmonary lipidosis and enhanced innate immune responses in the airway. Whether ABCG1 regulates adaptive immune responses to the environment is unknown. To this end, Abcg1(+/+) and Abcg1(-/-) mice were sensitized to OVA via the airway using low-dose LPS as an adjuvant, and then challenged with OVA aerosol. Naive Abcg1(-/-) mice displayed increased B cells, CD4(+) T cells, CD8(+) T cells, and dendritic cells (DCs) in lung and lung-draining mediastinal lymph nodes, with lung CD11b(+) DCs displaying increased CD80 and CD86. Upon allergen sensitization and challenge, the Abcg1(-/-) airway, compared with Abcg1(+/+), displayed reduced Th2 responses (IL-4, IL-5, eosinophils), increased neutrophils and IL-17, but equivalent airway hyperresponsiveness. Reduced Th2 responses were also found using standard i.p. OVA sensitization with aluminum hydroxide adjuvant. Mediastinal lymph nodes from airway-sensitized Abcg1(-/-) mice produced reduced IL-5 upon ex vivo OVA challenge. Abcg1(-/-) CD4(+) T cells displayed normal ex vivo differentiation, whereas Abcg1(-/-) DCs were found paradoxically to promote Th2 polarization. Th17 cells, IL-17(+) γδT cells, and IL-17(+) neutrophils were all increased in Abcg1(-/-) lungs, suggesting Th17 and non-Th17 sources of IL-17 excess. Neutralization of IL-17 prior to challenge normalized eosinophils and reduced neutrophilia in the Abcg1(-/-) airway. We conclude that Abcg1(-/-) mice display IL-17-mediated suppression of eosinophilia and enhancement of neutrophilia in the airway following allergen sensitization and challenge. These findings identify ABCG1 as a novel integrator of cholesterol homeostasis and adaptive immune programs.
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Draper
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Madenspacher
authors.forename: Rhonda H
authors.initials: RH
authors.lastname: Wilson
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Whitehead
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakano
authors.forename: Arun R
authors.initials: AR
authors.lastname: Pandiri
authors.forename: Julie F
authors.initials: JF
authors.lastname: Foley
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D056704:Adaptive Immunity / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D055785:Gene Knockdown Techniques; D020381:Interleukin-17 / Q000502:physiology*; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D020381:Interleukin-17; D008074:Lipoproteins