Qu Xiaopeng, Tao Pengyu, Dong Jiajia, Meng Lingzhao
Department of Otolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Department of Otolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Int Immunopharmacol. 2025 Sep 23;162:115120. doi: 10.1016/j.intimp.2025.115120. Epub 2025 Jun 21.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is chronic respiratory disease with high prevalence worldwide, especially in old people. Macrophage polarization-mediated inflammation and nasal mucosal epithelium remodeling are potential etiologic factors for CRSwNP. Quercetin is a natural plant-derived flavonoid and exerts the important function in chronic inflammatory disease. Nevertheless, its roles in CRSwNP remain elusive. The current study confirmed the higher levels of CD68CD206 M2 macrophages in CRSwNP patients relative to the control groups, but not changes in the contents of CD68CD80 M1 macrophages. Moreover, quercetin restrained IL-4-evoked increases in the numbers of CD68CD206 M2 macrophage, concomitant with the decrease in M2 macrophage marker CD206, CD163, MMP-9 and TGF-β expression. Moreover, the increased releases of chemokine CCL-18, CCL-24 and CCL-13 from M2 macrophages were reduced by quercetin. Furthermore, human nasal epithelial cells (hNECs) underwent epithelial-mesenchymal transition (EMT) occurrence after co-cultured with M2-like macrophages by decreasing E-cadherin expression and increasing vimentin expression. However, M2 macrophages-induced EMT in hNECs was reversed by quercetin treatment. Mechanistically, quercetin mitigated activation of the JAK2/STAT3 pathway in M2-like macrophages. Intriguingly, re-activating the above pathway via its activator RO8191 reversed quercetin-mediated inhibition in macrophage M2 polarization and their polarization-mediated EMT in hNECs. In vivo, Quercetin alleviated the progression of CRSwNP in mice model by attenuating nasal symptoms, polyp formation and inflammation. Moreover, administration with quercetin decreased the levels of CD68CD206 M2-like macrophages and chemokine in nasal mucosa tissues in CRSwNP mice model. Simultaneously, quercetin attenuated nasal mucosal remodeling by inhibiting EMT and MMP-2, MMP-9 levels. Re-activating the JAK2/STAT3 pathway antagonized quercetin-mediated protective efficacy against CRSwNP. Thus, quercetin may alleviate the progression of CRSwNP by regulating macrophage M2 polarization and nasal mucosal remodeling via the blockage of the JAK/STAT3 pathway, supporting a promising agent against CRSwNP.
伴鼻息肉的慢性鼻窦炎（CRSwNP）是一种慢性呼吸道疾病，在全球范围内，尤其是在老年人中，患病率很高。巨噬细胞极化介导的炎症和鼻黏膜上皮重塑是CRSwNP的潜在病因。槲皮素是一种天然植物来源的黄酮类化合物，在慢性炎症性疾病中发挥重要作用。然而，其在CRSwNP中的作用仍不明确。目前的研究证实，与对照组相比，CRSwNP患者中CD68⁺CD206⁺ M2巨噬细胞水平更高，但CD68⁺CD80⁺ M1巨噬细胞的含量没有变化。此外，槲皮素抑制了IL-4诱导的CD68⁺CD206⁺ M2巨噬细胞数量增加，同时M2巨噬细胞标志物CD206、CD163、MMP-9和TGF-β的表达也降低。此外，槲皮素降低了M2巨噬细胞趋化因子CCL-18、CCL-24和CCL-13的释放增加。此外，人鼻上皮细胞（hNECs）与M2样巨噬细胞共培养后，通过降低E-钙黏蛋白表达和增加波形蛋白表达，发生上皮-间质转化（EMT）。然而，槲皮素处理可逆转M2巨噬细胞诱导的hNECs中的EMT。机制上，槲皮素减轻了M2样巨噬细胞中JAK2/STAT3通路的激活。有趣的是，通过其激活剂RO8191重新激活上述通路，可逆转槲皮素介导的对巨噬细胞M2极化及其在hNECs中极化介导的EMT的抑制作用。在体内，槲皮素通过减轻鼻症状、息肉形成和炎症，缓解了小鼠模型中CRSwNP的进展。此外，在CRSwNP小鼠模型中，给予槲皮素可降低鼻黏膜组织中CD68⁺CD206⁺ M2样巨噬细胞和趋化因子的水平。同时，槲皮素通过抑制EMT以及MMP-2、MMP-9水平，减轻鼻黏膜重塑。重新激活JAK2/STAT3通路可拮抗槲皮素介导的对CRSwNP的保护作用。因此，槲皮素可能通过阻断JAK/STAT3通路调节巨噬细胞M2极化和鼻黏膜重塑，从而缓解CRSwNP的进展，有望成为治疗CRSwNP的药物。
