Role of C3a as a Novel Regulator of 25(OH)D3 to 1α,25-Dihydroxyvitamin D3 Metabolism in Upper Airway Epithelial Cells

Abstract

In patients with chronic rhinosinusitis with nasal polyps, primary human sinonasal epithelial cell (HSNEC) 1α-hydroxylase levels are reduced, as is their ability to metabolize 25-hydroxycholecalciferol [25(OH)D₃] to its active metabolite, 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. In this study, we sought to identify the factor responsible for the regulation of HSNEC metabolism of 25(OH)D₃, focusing on C3 and C3a. Multiple inhaled irritants trigger the release of complement components, C3 and C3a, leading to suppression of 1α-hydroxylase levels in HSNECs. Recombinant C3a was able to decrease 1α-hydroxylase and impair 25(OH)D₃ to 1,25(OH)₂D₃ metabolism, while addition of a C3a receptor antagonist restored conversion. Conversely, 1,25(OH)₂D₃ suppressed Aspergillus fumigatus-induced C3 and C3a levels in HSNEC supernatant. Given the ability of 1,25(OH)₂D₃ to modulate LL37 in other cell types, we examined its regulation in HSNECs and relationship to C3a. 1,25(OH)₂D₃ stimulated the secretion of LL37, whereas A. fumigatus and C3a suppressed it. Conversely, LL37 reduced the release of C3/C3a by HSNECs. Lastly, oral steroid use and in vitro dexamethasone application both failed to increase 1α-hydroxylase or reduce C3a levels. In summary, in this article, we describe for the first time a novel relationship between complement activation and local vitamin D metabolism in airway epithelial cells. The presence of elevated C3/C3a in patients with asthma and/or chronic rhinosinusitis with nasal polyps may account for their impaired HSNEC 25(OH)D₃ to 1,25(OH)₂D₃ metabolism and explain why they receive limited therapeutic benefit from oral vitamin D₃ supplementation.