Zhu Ying, Zhou Jiayao, Tang Ru, Zhang Shiyao, Luo Chunyu, Gu Yuelong, Pu Shilei, Mao Song, Lin Hai, Ye Haibo, Li Zhipeng, Zhang Weitian
Department of Otolaryngology-Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Otolaryngological Institute, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, PR China.
Department of Otolaryngology-Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Otolaryngological Institute, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, PR China; Department of Otolaryngology-Head and Neck Surgery, Shanghai Children's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Mucosal Immunol. 2025 Jul 19. doi: 10.1016/j.mucimm.2025.07.004.
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.
巨噬细胞表达的载脂蛋白E（APOE）可调节下呼吸道的过敏性炎症和重塑。然而，其在伴鼻息肉的慢性鼻-鼻窦炎（CRSwNP）中的表达及功能仍不清楚。我们试图研究巨噬细胞源性APOE在CRSwNP发病机制中的作用。在单细胞RNA测序数据中评估APOE表达，然后在健康对照（HC）、无鼻息肉的慢性鼻-鼻窦炎（CRSsNP）和CRSwNP患者的组织中进行验证。我们发现，嗜酸性和非嗜酸性CRSwNP患者的M2巨噬细胞中APOE表达均升高。与HC和CRSsNP患者相比，CRSwNP患者鼻分泌物中的APOE蛋白增加，而血清样本中未发现显著差异。TGF-β在体外诱导THP-1和外周血单核细胞（PBMC）分化的巨噬细胞分泌APOE。预测成纤维细胞LRP1为潜在受体，其表达与APOE水平呈正相关。在原代鼻成纤维细胞中，APOE通过LRP1依赖的ERK激活诱导MMP2和MMP9表达。在野生型和Apoe基因敲除小鼠中建立CRSwNP小鼠模型，结果表明Apoe基因敲除减弱了NP样病变的形成以及鼻黏膜中Lrp1和Mmp2的表达。我们的数据表明，嗜酸性和非嗜酸性CRSwNP患者巨噬细胞中的APOE表达增加，并通过LRP1-ERK信号促进成纤维细胞MMP2和MMP9表达，这可能有助于CRSwNP中的组织重塑。
