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

Abstract

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. 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. 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. 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. T3 and neutrophilic inflammation induce different molecular pathways resulting in distinct clinical presentations in T2 CRSwNP.