IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2–type 3 inflammation in nasal polyps - 05/05/26
, Luo Zhang, MD, PhD a, b, d, ⁎ , Claus Bachert, MD, PhD eGraphical abstract |
Abstract |
Background |
Chronic rhinosinusitis with nasal polyps involves mixed type 2–type 3 inflammation, associated with disease severity and treatment resistance, yet mechanisms remain unclear.
Objective |
We sought to investigate the role of IL-2 and its interaction with type 3 inducers (TNF-α, IL-1β, and IL-23) in driving mixed type 2–type 3 inflammation.
Methods |
IL-2 and receptor expression in nasal polyps was analyzed using tissue homogenates and public RNA-sequencing data. Dispersed nasal polyp cells were treated with IL-2/type 3 inducers, with cytokine production, proliferation, and gene expression analyzed via immunoassays, flow cytometry, and RNA sequencing. IL-2 receptor/Janus kinase (JAK) blockade studies were conducted. Furthermore, CD4 + and CD8 + T cells were magnetically isolated from nasal polyps to evaluate their response to cytokine stimulation.
Results |
IL-2 levels were increased in chronic rhinosinusitis with nasal polyps, particularly in type 3–dominant and mixed type 2–type 3 subgroups, and correlated with type 3 cytokines. RNA sequencing supported upregulated IL-2 receptors and their coexpression with type 3 genes. IL-2 synergized with type 3 inducers to enhance both type 2 and type 3 cytokine production in dispersed nasal polyp cells. Direct functional evidence from isolated CD4 + and CD8 + T cells confirmed this synergy, with CD8 + T cells emerging as a novel source of IL-13. Flow cytometry further supported these findings, showing synergistic cytokine production across diverse cell populations, including T-cell subsets and natural killer cells. Memory T cells mediated T-cell receptor–independent cytokine production. Transcriptomic analysis identified activated type 3, type 2, and JAK–signal transducer and activator of transcription signaling pathways. IL-2 receptor blockade, particularly JAK inhibition, attenuated IL-2/type 3 inducer–mediated synergistic inflammation.
Conclusions |
A novel mechanism was identified whereby IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2–type 3 inflammation via innate-like T-cell activation, and targeted JAK inhibition was validated as a potential therapy.
Le texte complet de cet article est disponible en PDF.Key words : Chronic rhinosinusitis with nasal polyps, mixed type 2–type 3 inflammation, IL-2, type 3 inducers, JAK-STAT signaling pathway
Abbreviations used : CRSsNP, CRSwNP, DEG, DNPC, ILC2, JAK, NK, NP, RUX, STAT, TCR
Plan
Vol 157 - N° 5
P. 1071-1086 - mai 2026 Retour au numéro
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