C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis

Jennifer K. Mulligan, Kunal Patel, Tucker Williamson, Nicholas Reaves, William Carroll, Sarah E. Stephenson, Peng Gao, Richard R. Drake, Benjamin A. Neely, Stephen Tomlinson, Rodney J. Schlosser, Carl Atkinson

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease with an unknown etiology. Recent studies have implicated the complement system as a potential modulator of disease immunopathology. We performed proteomic pathway enrichment analysis of differentially increased proteins, and found an enrichment of complement cascade pathways in the nasal mucus of individuals with CRSwNP as compared to control subjects. Sinonasal mucus levels of complement 3 (C3) correlated with worse subjective disease severity, whereas no significant difference in systemic C3 levels could be determined in plasma samples. Given that human sinonasal epithelial cells were the predominate sinonasal source of C3 and complement anaphylatoxin 3a (C3a) staining, we focused on their role in in vitro studies. Baseline intracellular C3 levels were higher in CRSwNP cells, and following exposure to Aspergillus fumigatus (Af) extract, they released significantly more C3 and C3a. Inhibition of complement 3a receptor (C3aR) signaling led to a decrease in Af-induced C3 and C3a release, both in vitro and in vivo. Finally, we found in vivo that C3aR deficiency or inhibition significantly reduced inflammation and CRS development in a mouse model of Af-induced CRS. These findings demonstrate that local sinonasal complement activation correlates with subjective disease severity, and that local C3aR antagonism significantly ameliorates Af-induced CRS in a rodent model.

Original languageEnglish (US)
Pages (from-to)1375-1385
Number of pages11
JournalMucosal Immunology
Volume11
Issue number5
DOIs
Publication statusPublished - Sep 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mulligan, J. K., Patel, K., Williamson, T., Reaves, N., Carroll, W., Stephenson, S. E., ... Atkinson, C. (2018). C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis. Mucosal Immunology, 11(5), 1375-1385. https://doi.org/10.1038/s41385-018-0048-x