C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis

Published

June 15, 2018

Author(s)

Jennifer K. Mulligan, Tucker Williamson, Nicholas Reaves, William Carroll, Sarah Stephenson, Peng Gao, Richard R. Drake, Ben Neely, Rodney J. Schlosser, Carl Atkinson

Abstract

Background: Innate immune factors, including the complement system, have been implicated in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Here we examine complement activity within the respiratory mucosa of CRSwNP patients, and a murine model of CRS, to determine the role of the complement anaphylatoxin, C3a, in CRS-associated inflammation. Objective: To determine the impact of local sinonasal complement production on sinonasal inflammation and to explore the therapeutic efficacy of complement inhibition in CRS. Methods: Complement protein expression was examined by ELISA, proteomics and flow cytometry in samples from patients with CRSwNP, or individuals who were undergoing endoscopic sinus surgery for non-inflammatory conditions, which served as controls. Primary human sinonasal epithelial cells (HSNEC) were cultured from tissue explants. The role of C3a, and therapeutic potential of C3a receptor antagonist were explored in a murine Aspergillus fumigatus model of (Af-CRS). Results: Pathway enrichment of differentially increased proteins found they were enriched in the complement cascade pathway in nasal mucus of individuals with CRSwNP. CRSwNP had significantly increased C3 concentrations in sinonasal mucus compared to controls, and correlated with worse subjective disease severity. CRSwNP-derived HSNEC had heightened intracellular stores of C3 and C3a versus controls. C3aR deficiency or treatment with C3aR-antagonist, systemically or locally by intra nasal route, significantly reduced inflammation and CRS development in a murine model of disease. Conclusions: C3 produced by sinonasal epithelia plays a crucial role in the pathogenesis of CRS. Further, our results suggest the novel possibility of treating CRSwNP with sinonasal delivery of complement therapeutics.

Citation

Journal of Allergy and Clinical Immunology

Volume

11

Pub Type

Journals

Download Paper

https://dx.doi.org/10.1038/s41385-018-0048-x

Local Download

Keywords

Complement, sinusitis, epithelial cell, inflammation, animal models

Citation

Mulligan, J. , Williamson, T. , Reaves, N. , Carroll, W. , Stephenson, S. , Gao, P. , Drake, R. , Neely, B. , Schlosser, R. and Atkinson, C. (2018), C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis, Journal of Allergy and Clinical Immunology, [online], https://dx.doi.org/10.1038/s41385-018-0048-x , https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=923243 (Accessed December 13, 2024)