C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis

Mucosal Immunol. 2018 Sep;11(5):1375-1385. doi: 10.1038/s41385-018-0048-x. Epub 2018 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillus fumigatus / pathogenicity
  • Cell Line
  • Chronic Disease
  • Complement C3 / metabolism
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Nasal Mucosa / drug effects
  • Nasal Mucosa / immunology
  • Nasal Polyps / drug therapy
  • Nasal Polyps / immunology
  • Proteome / immunology
  • Receptors, Complement / antagonists & inhibitors*
  • Rhinosporidiosis / drug therapy*
  • Rhinosporidiosis / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology


  • Complement C3
  • Proteome
  • Receptors, Complement
  • complement C3a receptor