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

Area of Science:

• Immunology
• Allergic Inflammation
• Epithelial Biology

Background:

• Allergic rhinitis (AR) is characterized by epithelial remodeling, particularly basal cell hyperplasia.
• The upstream drivers and mechanisms of AR-related epithelial remodeling are not fully understood.

Purpose of the Study:

• To investigate the role of complement component 3 (C3) and C3a-C3a receptor (C3aR) signaling in AR epithelial remodeling.
• To explore the impact of C3/C3aR signaling on macrophage-mediated inflammation and metabolic reprogramming in AR.

Main Methods:

• Transcriptome sequencing of nasal mucosa from AR patients and controls.
• Evaluation of epithelial remodeling in AR patients, a mouse model, and cell cultures.
• Utilized C3-deficient mice and a C3aR antagonist to assess C3/C3aR signaling effects.
• Investigated fatty acid oxidation (FAO) and PCCB in macrophage activation.

Main Results:

• AR nasal mucosa showed increased epithelial remodeling and basal cell hyperplasia.
• C3 was the most upregulated complement gene in AR mucosa, correlating with disease severity.
• C3 deficiency or C3aR antagonism reduced AR-associated epithelial remodeling, hyperplasia, and inflammation.
• C3a-C3aR signaling promoted CD206+ macrophages with a lipid metabolic program.
• Inhibition of FAO or PCCB attenuated C3aR-driven macrophage activation and subsequent epithelial remodeling via TGF-β1.

Conclusions:

• C3/C3a-C3aR signaling is a key driver of epithelial remodeling in allergic rhinitis.
• This signaling pathway promotes macrophage lipid metabolic reprogramming, contributing to AR pathogenesis.