Kobayashi Yoshiki, Hanh Chu Hong, Yagi Naoto, Le Nhi Kieu Thi, Yun Yasutaka, Shimamura Akihiro, Fukui Kenta, Mitani Akitoshi, Suzuki Kensuke, Kanda Akira, Iwai Hiroshi
Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan.
Cells. 2024 Dec 31;14(1):33. doi: 10.3390/cells14010033.
Eosinophilic chronic rhinosinusitis (ECRS), a CRS with nasal polyps (CRSwNP), is characterized by eosinophilic infiltration with type 2 inflammation and is highly associated with bronchial asthma. Intractable ECRS with poorly controlled asthma is recognized as a difficult-to-treat eosinophilic airway inflammation. Although eosinophils are activated and coincubation with airway epithelial cells prolongs their survival, the interaction mechanism between eosinophils and epithelial cells is unclear. This study examined the effect of eosinophils on mucin glycoprotein 1 (MUC1), a member of membrane-bound mucin, in the airway epithelial cells, to elucidate the mechanisms of the eosinophil-airway epithelial cell interaction. Nasal polyp samples from patients with CRSwNP and BEAS-2B airway epithelial cells, coincubated with purified eosinophils, were stained with two MUC1 antibodies. To confirm the involvement of CCL4, an anti-CCL4 neutralizing antibody or recombinant CCL4 was used as needed. The immunofluorescence results revealed a negative correlation between the expression of full-length MUC1 and eosinophil count in nasal polyps. In BEAS-2B coincubated with eosinophils, full-length MUC1, but not the C-terminal domain, was reduced, and eosinophil survival was prolonged, which was concomitant with CCL4 increase, whereas the anti-CCL4 neutralizing antibody decreased these reactions. The survival of eosinophils that contacted recombinant MUC1 without the N-terminal domain was prolonged, and recombinant CCL4 increased the expression of metalloproteases. Increased CCL4 induces the contact between eosinophils and airway epithelial cells by shedding the MUC1 N-terminal domain and enhances eosinophil survival in eosinophilic airway inflammation. This novel mechanism may be a therapeutic target for difficult-to-treat eosinophilic airway inflammation.
嗜酸性粒细胞性慢性鼻-鼻窦炎（ECRS）是一种伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP），其特征为嗜酸性粒细胞浸润并伴有2型炎症，且与支气管哮喘高度相关。难治性ECRS合并哮喘控制不佳被认为是一种难以治疗的嗜酸性粒细胞性气道炎症。尽管嗜酸性粒细胞被激活，并且与气道上皮细胞共孵育可延长其存活时间，但嗜酸性粒细胞与上皮细胞之间的相互作用机制尚不清楚。本研究检测了嗜酸性粒细胞对气道上皮细胞中膜结合黏蛋白成员黏蛋白糖蛋白1（MUC1）的影响，以阐明嗜酸性粒细胞与气道上皮细胞相互作用的机制。来自CRSwNP患者的鼻息肉样本以及与纯化的嗜酸性粒细胞共孵育的BEAS-2B气道上皮细胞，用两种MUC1抗体进行染色。为证实CCL4的参与，根据需要使用抗CCL4中和抗体或重组CCL4。免疫荧光结果显示鼻息肉中全长MUC1的表达与嗜酸性粒细胞计数呈负相关。在与嗜酸性粒细胞共孵育的BEAS-2B细胞中，全长MUC1减少，而C末端结构域未减少，嗜酸性粒细胞存活时间延长，同时CCL4增加，而抗CCL4中和抗体可减弱这些反应。与不含N末端结构域的重组MUC1接触的嗜酸性粒细胞存活时间延长，重组CCL4增加了金属蛋白酶的表达。CCL4增加通过脱落MUC1的N末端结构域诱导嗜酸性粒细胞与气道上皮细胞接触，并增强嗜酸性粒细胞在嗜酸性粒细胞性气道炎症中的存活。这种新机制可能为难治性嗜酸性粒细胞性气道炎症的治疗靶点。
