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.
Bibliographical noteFunding Information:
These studies were funded by grants from the NIH to C.A. (R01HL091944), Flight Attendants Medical Research Institute Clinical Innovator award 092079 (C.A.) and 92401 (J.K.M.). J.K.M. is supported by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, NIH/NCATS Grant Numbers KL2 TR001452 and UL1 TR001450. This work was supported in part by core funds from the Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and the MUSC Proteomics Center, South Carolina Centers for Economic Excellence SmartState program. B.A.N. was supported in part by an award to the South Carolina SmartState Center of Economic Excellence in Proteomics, the Medical University of South Carolina Proteomics Center, and P20GM103542 from the NIGMS.
© 2018, Society for Mucosal Immunology.