ArticleJournal of translational medicine2025
The role of substance P in Th17/Treg imbalance and ocular surface damage in chronic allergic conjunctivitis.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAllergic conjunctivitis (AC) is a prevalent ocular surface disorder, with chronic or severe manifestations of AC frequently resulting in substantial ocular surface damage. The neuropeptide substance P (SP) plays a critical role in inflammation and immune regulation; however, its involvement in AC remains unclear. The objective of this study was to establish a murine model of persistent AC through repeated allergen exposure to investigate how SP and its downstream STAT3/STAT5 pathway modulate Th17/Treg imbalance and exacerbate ocular surface damage.
methodsA persistent AC mouse model was established through repeated ovalbumin (OVA) challenges. The ocular surface damage in the mice was evaluated using slit lamp examination, H&E staining, fluorescein staining, PAS staining, and TUNEL staining. The percentages of Th17/Treg cells and the expression of associated proteins (IL-17 and FOXP3) in cervical lymph nodes and conjunctival-corneal tissues were assesed using flow cytometry, immunofluorescence and Western blot. RNA sequencing was subsequently conducted to identify differentially expressed genes. The expression of substance P (SP) and its receptor (NK1R) was validated using a reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence and immunohistochemistry. SP and the NK1R antagonist Spantide II were administered to examine their effects on Th17/Treg balance and STAT3/STAT5 signaling (pSTAT3/pSTAT5).
resultsExposure to continuous OVA induced severe allergic symptoms, such as eyelid swelling and conjunctival hyperaemia, as well as ocular surface damage. This damage included inflammatory infiltration, corneal barrier dysfunction, loss of goblet cells and apoptosis. The number of Th17 cells increased while the number of Tregs decreased, resulting in an elevated Th17/Treg ratio. RNA-seq revealed that SP expression was upregulated in the conjunctiva of AC, correlating with sensitization frequency; a similar trend was observed for NK1R. Both in vitro and in vivo experiments confirmed that SP exacerbated the Th17/Treg imbalance by promoting Th17 differentiation and inhibiting Treg differentiation while also activating the STAT3/STAT5 signaling pathway, as evidenced by increased pSTAT3 and decreased pSTAT5 levels. Intervention with Spantide II markedly alleviated ocular inflammation, restored corneal integrity, reduced apoptosis, rebalanced Th17/Treg ratios, and suppressed STAT3/STAT5 activation.
conclusionsSubstance P contributes to persistent AC by disrupting the Th17/Treg equilibrium via STAT3/STAT5 signaling, thereby exacerbating ocular surface damage. Targeting the SP/NK1R pathway may offer a novel therapeutic approach for chronic AC.
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