title: Dopamine D1-like receptor antagonist attenuates Th17-mediated immune response and ovalbumin antigen-induced neutrophilic airway inflammation.
abstract: Allergic airway inflammation is generally considered a Th2-type immune response. Recent studies, however, demonstrated that Th17-type immune responses also play important roles in this process, especially in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We previously reported that dendritic cells release dopamine to naive CD4(+) T cells in Ag-specific cell-cell interaction, in turn inducing Th17 differentiation through dopamine D1-like receptor (D1-like-R). D1-like-R antagonist attenuates Th17-mediated diseases such as experimental autoimmune encephalomyelitis and autoimmune diabetes. However, the effect of antagonizing D1-like-R on Th17-mediated airway inflammation has yet to be studied. In this study, we examined whether D1-like-R antagonist suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice and then elucidated the mechanism of action. DO11.10 mice were nebulized with OVA or PBS, and some mice received D1-like-R antagonist orally before OVA nebulization. D1-like-R antagonist significantly suppressed OVA-induced neutrophilic airway inflammation in DO11.10 mice. It also inhibited the production of IL-17 and infiltration of Th17 cells in the lung. Further, D1-like-R antagonist suppressed the production of IL-23 by lung CD11c(+) APCs. In contrast, D1-like-R antagonist did not increase Foxp3(+) regulatory T cells in the lung. D1-like-R antagonist neither suppressed nonspecific LPS-induced neutrophilic airway inflammation nor OVA-induced eosinophilic airway inflammation. These results indicate that D1-like-R antagonist could suppress Th17-mediated neutrophilic airway inflammation, raising the possibility that antagonizing D1-like-R serves as a promising new strategy for treating neutrophil-dominant severe asthma.
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama 350-0495, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Imamura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okada
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Inoue
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Harada
authors.forename: Takehiro
authors.initials: T
authors.lastname: Higashi
authors.forename: Rie
authors.initials: R
authors.lastname: Takagi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Minoru
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Dohi
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagata
authors.forename: Sho
authors.initials: S
authors.lastname: Matsushita
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004298:Dopamine / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D053759:Interleukin-23 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D001552:Benzazepines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053759:Interleukin-23; D008070:Lipopolysaccharides; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D010047:Ovalbumin; D004298:Dopamine