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.

Persistent elevation of blood pressure by ambient coarse particulate matter after recovery from pulmonary inflammation in mice

“…Their lungs were lavaged with 1mL saline and the recovered amount of lavagate was recorded and stored. The total cell count and cell type distribution in BALF were determined as previously described . Protein concentrations of BALF were measured using the Bradford assay (Bio‐Rad, Hercules, California).…”

“…Tissue processing was followed by dehydration, clearing, and embedding. Hematoxylin and eosin staining was used for general histopathological examinations as previously described …”

“…Hematoxylin and eosin staining was used for general histopathological examinations as previously described. 40,41 2.10 | Enzyme-linked immunosorbent assays OPN, vascular cell adhesion protein 1 (VCAM-1), ICAM-1, CRP, ET-1, interleukin-6 (IL-6), keratinocyte-derived chemokine (KC), chemokine (C-C motif) ligand 5 (CCL5), and metalloproteinase (MMP)-8, -9, and -12 were quantified in BALF or serum samples using the commercial sensitive and specific enzyme-linked immunosorbent assay kits for mice (R&D Systems, Inc, Minneapolis, Minnesota) in accordance with the manufacturer's instructions.…”

Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials

“…Recent studies have shown that AhR is not only involved in metabolizing toxicants but may also be involved in the pulmonary immune and pro-inflammatory responses [ 124 ]. For example, a study using AhR KO mice exposed to ZnONPs via oropharyngeal aspiration ( Table 3 ) showed that these mice had reduced cell numbers, total protein, LDH activity, and pro-inflammatory cytokine production in BALF compared to the wild type mice [ 125 ]. No increase in CYP1A1, a downstream target of AhR, was detected in AhR KO mice [ 125 ].…”

“…For example, a study using AhR KO mice exposed to ZnONPs via oropharyngeal aspiration ( Table 3 ) showed that these mice had reduced cell numbers, total protein, LDH activity, and pro-inflammatory cytokine production in BALF compared to the wild type mice [ 125 ]. No increase in CYP1A1, a downstream target of AhR, was detected in AhR KO mice [ 125 ]. In addition, AhR KO mice did not display an increase in kynurenine (KYN), which is an endogenous AhR agonist [ 125 ].…”