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

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)D] to its active metabolite, 1α,25-dihydroxyvitamin D [1,25(OH)D]. In this study, we sought to identify the factor responsible for the regulation of HSNEC metabolism of 25(OH)D, 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)D to 1,25(OH)D metabolism, while addition of a C3a receptor antagonist restored conversion. Conversely, 1,25(OH)D suppressed -induced C3 and C3a levels in HSNEC supernatant. Given the ability of 1,25(OH)D to modulate LL37 in other cell types, we examined its regulation in HSNECs and relationship to C3a. 1,25(OH)D stimulated the secretion of LL37, whereas 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)D to 1,25(OH)D metabolism and explain why they receive limited therapeutic benefit from oral vitamin D supplementation.