Effects of type 3 and neutrophilic inflammation on type 2 chronic rhinosinusitis with nasal polyps

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BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is most commonly divided into 3 endotypes (type 1 [T1], T2, and T3) on the basis of the T-cell cytokine profiles. Although neutrophils are classically associated with T3 inflammation in chronic rhinosinusitis, neutrophilic infiltration can be present without a T3 signal. OBJECTIVE: We sought to identify the effects of T3 and neutrophilic (called neutrophil variant or Vneut) inflammation on clinical presentations and phenotype-associated mechanisms in patients with T2 CRSwNP. METHODS: We obtained 66 control ethmoid tissues and 158 nasal polyps (NPs). We measured mRNA markers for T1, T2, T3, and Vneut inflammation by quantitative RT-PCR and whole RNA expression profiles by bulk RNA sequencing. We investigated associations between the endotypes and natural histories and predicted molecular pathways by gene enrichment analysis. RESULTS: Because 96% of the NPs had T2 endotype, most T1, T3, and Vneut inflammation coexisted with T2 endotype. Recurrent NP was associated with mixed T2 + T3 (P = .012) as well as T2 + Vneut (P = .022) inflammation, whereas sinus computed tomography and NP scores were associated only with T2 + Vneut inflammation (P < .05). Compared with control tissues, we identified shared and specific dysregulated genes in T2 single, T2 + T3, and T2 + Vneut mixed endotypes, and the results suggest that NP recurrence (T2 + T3 and T2 + Vneut shared dysregulated genes) was associated with activation of cytotoxic T cells and M1 macrophages, whereas sinus computed tomography and NP scores (T2 + Vneut-specific genes) were associated with activation of neutrophils, M2 macrophages, and fibroblasts as well as with downregulation of innate host defense. CONCLUSIONS: T3 and neutrophilic inflammation induce different molecular pathways resulting in distinct clinical presentations in T2 CRSwNP.

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