Abnormal purine metabolism in nasal epithelial cells affects allergic rhinitis by regulating Th17/Treg cells.

Abstract

We aimed to explore novel pathogenesis in young children with allergic rhinitis (AR), and thus finding novel nasal spray reagents for them, especially under 4 yr old. In this study, nontargeted metabolomics analyses were used to explore the differential metabolites in nasal lavage fluid (NALF) of children with AR. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to assess cell proliferation and apoptosis in human nasal mucosal epithelial cells (HNEpCs). HNEpCs were cocultured with CD4⁺ T cells, and flow cytometry was used to detect Th17/regulatory T (Treg) cells. RNA sequencing was used to assess the key pathways in xanthine-treated Jurkat T cells. Finally, both the in vitro and in vivo experiments were used to assess the effect of 1, 3-dipropyl-8 cyclopentylxanthine (DPCPX, Adora1 inhibitor) on activating transcription factor 4 (ATF4) expression and Th17/Treg cells. Xanthine and uric acid levels were increased in the NALF of children with AR. Xanthine dehydrogenase (XDH), purine nucleoside phosphatase (PNP), xanthine/hypoxanthine, and uric acid levels were elevated in Derp1-treated HNEpCs, and si-XDH reversed the reduced cell viability and increased cell apoptosis in Derp1-treated HNEpCs. Both xanthine and Derp1-treated HNEpCs increased the Th17/Treg ratio. The endoplasmic reticulum stress (ERS) pathway was affected in xanthine-treated Jurkat T cells, and ATF4 was markedly reduced in xanthine-treated Jurkat T cells. Xanthine exhibited no effect on Adora1 expression, whereas DPCPX elevated ATF4 expression and reduced the Th17/Treg ratio in xanthine-treated Jurkat T cells. The in vitro experiments revealed that DPCPX reduced inflammatory infiltration, Th17/Treg ratio, interleukin (IL)-17, tumor necrosis factor (TNF)-α, and IL-6 in AR mice. These results demonstrated that xanthine inhibited ATF4 expression via Adora1 to elevate the Th17/Treg ratio in the nasal cavity, thus participating in AR progression. These findings may provide novel therapeutic interventions for young children with AR.NEW & NOTEWORTHY Current nasal spray hormones exhibited some adverse reactions for young children with allergic rhinitis (AR), and there were no suitable nasal spray hormones for children with AR under 4 yr old. This study emphasized the important role of purine metabolism in the nasal cavity in children with AR and provided novel therapeutic interventions for children with AR.