title: Involvement of the cytokine-IDO1-AhR loop in zinc oxide nanoparticle-induced acute pulmonary inflammation.
abstract: Zinc oxide nanoparticles (ZnONPs) are widely used in our daily life, such as in sunscreens and electronic nanodevices. However, pulmonary exposure to ZnONPs causes acute pulmonary inflammation, which is considered as an initial event for various respiratory diseases. Thus, elucidation of the underlying cellular mechanisms of ZnONPs can help us in predicting their potential effects in respiratory diseases. In this study, we observed that ZnONPs increased proinflammatory cytokines, accompanied with an increased expression of aryl hydrocarbon receptor (AhR) and its downstream target cytochrome P450 1A1 (CYP1A1) in macrophages in vitro and in mouse lung epithelia in vivo. Moreover, zinc nitrate, but not silica or titanium dioxide nanoparticles (NPs), had similar effects on macrophages, indicating that the zinc element or ion released from ZnONPs is likely responsible for the activation of the AhR pathway. Cotreatment with an AhR antagonist or AhR knockout reduced ZnONPs-induced cytokine secretion in macrophages or mice, respectively. Furthermore, kynurenine (KYN), an endogenous AhR agonist and a tryptophan metabolite catalyzed by indoleamine 2,3-dioxygenase (IDO), was increased in the serums of mice that aspirated ZnONPs. Consistently, ZnONPs increased IDO1 expression in lung cells in vitro and in vivo. Finally, AhR knockout reduced ZnONPs-induced pulmonary inflammation, cytokine secretion and KYN production in mice, suggesting that AhR activation is involved in ZnONPs-induced cytokine secretion and pulmonary inflammation. In summary, we demonstrated that the pulmonary exposure of ZnONPs stimulated the cytokine-IDO1-AhR loop in the lungs, which has been implied to play roles in immune dysfunctions.
authors.affiliation: a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ho
authors.affiliation: b Department of Chemistry , Fu Jen Catholic University , New Taipei City , Taiwan.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.affiliation: b Department of Chemistry , Fu Jen Catholic University , New Taipei City , Taiwan.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.
authors.forename: Yueh-Hsia
authors.initials: YH
authors.lastname: Luo
authors.affiliation: a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.
authors.forename: Hui-Ti
authors.initials: HT
authors.lastname: Tsai
authors.affiliation: a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015034:Zinc Oxide / Q000633:toxicity*
chemical_list: D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018336:Receptors, Aryl Hydrocarbon; D015034:Zinc Oxide
keywords: AhR; ZnONPs; cytokine–IDO1–AhR loop; inflammation