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 The purpose of this study was 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 brushes 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, chronic rhinosinusitis 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 (PGE2) activation signature. The Lund-McKay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, PGE2, and IL-13 and negatively with ciliated cell transcriptional signatures.

Conclusions These results demonstrate that cell type alterations and PGE2 stimulation are key components of IL-13 induced epithelial remodeling in nasal polyposis, while IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13 induced epithelial remodeling.

Key Messages

Cell type signatures from single cell RNA sequencing, applied to bulk sequenced RNA sinus brushes, suggest increased tuft cells and mast cells and decreased ciliated cells in nasal polyp epithelium.

IL-17 signaling rather than IL-13 signaling is observed in epithelium from CRSsNP.

IL-13-drives epithelial remodeling and prostaglandin E2 signatures correlated with clinical measures of sinus opacification in CRS.

Capsule Summary Measures of epithelial remodeling, including both IL-13 and PGE2 induced epithelial activation and cell type specific transcript alterations, correlate with a radiographic metric of disease severity in CRSwNP.

JGG is a Genentech Advisory Board Consultant with agreement ending December 2021. ANG is a minor stock holder in Siesta Medical. SDP and ANG are co-inventors of patent 14/394, 006 Sinus diagnostics and treatments. The other authors declare no competing interests.

This work was supported by the National Institutes of Health (5R01AI136962 to EDG; R01HL128439, R01HL135156, and P01HL132821 to MAS; F32HL140868 and T32HL007185 to MEK; F32HL158174 to CAS), the Department of Defense (MAS), the A.P. Giannini Foundation (MEK), the Webb-Waring Early Career Investigator Award from the Boettcher Foundation (CMM), the Nina Ireland Program for Lung Health at UCSF (EDG and MEK), the UCSF John A. Watson Faculty Scholar Fund (JGG), and the SABRE Center at UCSF (EDG).

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Ethics committee/IRB of the University of California, San Francisco gave ethical approval for this work.

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Funding This work was supported by the National Institutes of Health (5R01AI136962 to EDG; R01HL128439, R01HL135156, and P01HL132821 to MAS; F32HL140868 and T32HL007185 to MEK; F32HL158174 to CAS), the Department of Defense (MAS), the A.P. Giannini Foundation (MEK), the Webb-Waring Early Career Investigator Award from the Boettcher Foundation (CMM), the Nina Ireland Program for Lung Health at UCSF (EDG and MEK), the UCSF John A. Watson Faculty Scholar Fund (JGG), and the SABRE Center at UCSF (EDG).

Declaration of interests JGG is a Genentech Advisory Board Consultant with agreement ending December 2021. ANG is a minor stock holder in Siesta Medical. SDP and ANG are co-inventors of patent 14/394, 006 Sinus diagnostics and treatments. The other authors declare no competing interests.

All data produced in the present study are available upon reasonable request to the authors