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

BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is most commonly divided into 3 endotypes, type 1 (T1), T2 and T3 based on the T cell cytokine profiles. While neutrophils are classically associated with T3 inflammation in CRS, 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 Since 96% of the NPs had T2 endotype, most T1, T3 and Vneut coexisted with T2 endotype. Recurrent NP was associated with both T2+T3 (p=0.012) and T2+Vneut (p=0.022) mixed inflammation, while sinus CT and NP scores were only associated with T2+Vneut inflammation (p<0.05). Compared to 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, while sinus CT and NP scores (T2+Vneut-specific genes) were associated with activation of neutrophils, M2 macrophages and fibroblasts as well as down-regulation of innate host defense. CONCLUSIONS T3 and neutrophilic inflammation induce different molecular pathways resulting in distinct clinical presentations in T2 CRSwNP.