Complement C3 links epithelial remodeling and macrophage metabolic reprogramming in allergic rhinitis.

Abstract

Epithelial remodeling, especially basal cell hyperplasia (BCH), is a hallmark of allergic rhinitis (AR), yet the upstream drivers and their related mechanisms remain incompletely understood. We sought to investigate the role of complement C3 induction and downstream C3a-C3a receptor (C3aR) signaling in epithelial remodeling and macrophage-mediated inflammation in AR. Transcriptome sequencing was conducted on nasal mucosa from patients with AR and healthy control subjects. Epithelial remodeling was evaluated in patients, an AR mouse model, and an air-liquid interface culture of mouse nasal epithelial cells. C3-deficient (C3^-/-) mice and a C3aR antagonist were used to assess the impact of C3/C3a-C3aR signaling on epithelial remodeling, BCH, macrophage activation, and metabolic reprogramming. Fatty acid oxidation (FAO) and PCCB were targeted to define their functional contributions to macrophage activation. Nasal mucosa from patients with AR exhibited increased epithelial remodeling, particularly BCH. Transcriptome sequencing identified C3 as the most upregulated complement-related gene in AR mucosa, with expression positively correlating with disease severity, epithelial remodeling, and BCH. C3^-/- mice and C3aR antagonist treatment attenuated AR-associated epithelial remodeling, BCH, and type 2 inflammation. Mechanistically, C3a-C3aR signaling promoted a CD206⁺ macrophage phenotype and induced a lipid metabolic program enriched for lipid uptake, FAO, and lipid biosynthesis. Inhibition of FAO or PCCB knockdown attenuated C3a-C3aR signaling-driven macrophage activation that contributes to epithelial remodeling via TGF-β1. These findings suggest that C3/C3a-C3aR signaling drives epithelial remodeling in AR by promoting macrophage lipid metabolic reprogramming.