IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis

Abstract

Background: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described.

Objective: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS.

Methods: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls.

Results: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures.

Conclusions: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Keywords: Chronic rhinosinusitis; IL-13; endotype; epithelial remodeling; nasal polyposis; prostaglandin E2; type 2 inflammation.

FIG 1.

Bulk RNA sequencing suggests loss of ciliated cells and increase in tuft cells in CRSwNP. A, Cell-type signatures generated from scSeq were applied to 39 bulk RNA-sequenced endoscopic sinus brushings. B, Basal cell, (C) goblet secretory cell, (D) ciliated cell, (E) tuft cell, (F) neuroendocrine cell, and (G) ionocyte cell scores in sequenced sinus brushings.

FIG 2.

IL-13–driven inflammation dominates in nasal polyps, whereas IL-17–driven inflammation is found in CRSsNP. A, IL-13–responsive genes are increased in polyp epithelium compared with CRSsNP or controls. B, Composite “score” of genes in Fig 2, A. C, Increased expression of transcripts associated with mast cells in nasal polyps. D, Enrichment in IL-17 signaling in CRSsNP compared with polyp. E, IL-17 response signature is elevated in CRSsNP. F, Composite score of IL-17 epithelial response signature from Fig 2, E. G, Neutrophil signatures are unaltered in CRS.

FIG 3.

IL-13 and PGE2 signatures are associated with epithelial remodeling in CRS. Correlation of IL-13 score with transcripts associated with (A) tuft cells, (B) ciliated cells, (C) goblet secretory cells, and (D) mast cells. E, Correlation of polyp tuft cell score with IL-13 score. F, Increase in PGE2-response genes in CRS. G, Correlation between IL-13 score and PGE2 score. Correlation between PGE2 and (H) ciliated, (I) goblet secretory, and (J) mast cell scores in sinus.

FIG 4.

Cell-type composition changes and inflammatory scores correlate with sinus opacification in CRS. Correlations between LM score and (A) polyp tuft cell score, (B) ciliated cell score, (C) PGE2 score, (D) IL-13 score, (E) mast cell score, and (F) IL-17 score in CRS epithelial brushings.