M2 macrophage-derived Apolipoprotein E promotes fibroblast MMPs expression via LRP1-ERK signaling in chronic rhinosinusitis with nasal polyps

Apolipoprotein E (APOE) expressed by macrophages modulates allergic inflammation and remodeling of the lower airway. However, its expression and functions in chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. We sought to investigate the involvement of macrophage derived APOE in the pathogenesis of CRSwNP. APOE expression was evaluated in single cell RNA sequencing data and then validated in tissues from healthy controls (HCs), chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP patients. We found that APOE expression was elevated in M2 macrophages of both eosinophilic and non-eosinophilic CRSwNP patients. APOE protein was increased in nasal secretions from CRSwNP patients compared to HCs and CRSsNP patients, while no significant differences were found in serum samples. TGF-β induced APOE secretion in both THP-1 and peripheral blood mononuclear cell (PBMC) differentiated macrophages in vitro. Fibroblast LRP1 was predicted as a potential receptor, with expression correlating positively with APOE levels. In primary nasal fibroblasts, APOE induced MMP2 and MMP9 expression through LRP1-dependent ERK activation. CRSwNP murine model was established in wild type and Apoe^-/- mice, which indicated that Apoe deficiency attenuated NP-like lesions formation and the expression of Lrp1 and Mmp2 in nasal mucosa. Our data demonstrated that APOE expression is increased in macrophages from both eosinophilic and non-eosinophilic CRSwNP and promotes fibroblast MMP2 and MMP9 expression via LRP1-ERK signaling, which may contribute to tissue remodeling in CRSwNP.