C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis

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 preformed 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 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 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 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.

Linking Complement C3 and B Cells in Nasal Polyposis

“…The upregulated burden of complement components in nasal polyps raised the question of which cells are involved in the complement protein syntheses. Complement production has been described for several epithelial cells [19,33] to be higher in nasal polyps [19]. We could demonstrate immunohistochemical C3 deposition at the epithelium and in the lumen in nasal polyps, but also for the inferior turbinate.…”

“…Drouin et al demonstrated the importance of C3a-C3aR interaction for asthma and its Th2 response, whereas C3aR deficiency leads to a decrease in eosinophils and diminished Th2related cytokines [32]. Also, Mulligan et al published observations showing reduced inflammation during C3aR inhibition in an Aspergillus fumigatus-induced CRS mouse model [19], supporting the detected results and the importance of C3a-C3aR interaction in humans. Nevertheless, although we could not show a prominent role for C5a and associated C5aR-bearing cells in NP, others postulate a role for increased MAC-formation along the epithelium and blood vessels leading to damage and loss of function [22,23].…”

“…Nasal polyposis has a large immunologic background and especially the innate immune system is a promising field in unraveling the undiscovered aspects of this disease. So far, complement expression was shown to be upregulated in CRS(wNP) patients [ 19 – 21 ]. Anaphylatoxins were increased in nasal secretions of CRSwNP patients without displaying effects on serum levels [ 22 ].…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…Similarly, repeated intranasal inoculation of immunocompetent mice with A. fumigatus conidia exposing high levels of chitin skewed T-helper cells toward a type-2 allergic response [79]. Furthermore, genetic deficiency or functional inhibition of C3aR reduced inflammation and development of chronic rhinosinusitis in a murine model of sinonasal A. fumigatus infection [80]. Also, mice carrying a loss-of-function mutation in C5 were described to be more susceptible to Aspergillus infections in models of chronic systemic and pulmonary aspergillosis, likely due to defective C5a-dependent recruitment of neutrophils (where effective generation of this anaphylatoxin requires the AP), and, possibly, reduced MAC formation (particularly on germinating conidia and hyphae) [81].…”

Proteomics in Drug Development: The Dawn of a New Era?

“…Mulligan et al . investigated novel therapeutic targets for chronic rhinosinusitis with nasal polyps (CRSwNP), focusing on complement component C3.…”