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Isolation of Group 2 Innate Lymphoid Cells from Mouse Nasal Mucosa to Detect the Expression of CD226
Published on: May 10, 2022
IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation in nasal polyps
Min Wang1, Qinqin Zhang2, Yifei Wang2
1Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing Key Laboratory of New Medicine and Diagnostic Technology Research for Nasal Disease, Beijing Institute of Otolaryngology, Beijing, China.
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.
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