Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis
Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis
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DOI：
10.1016/j.jaci.2019.12.893
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发表时间：
2020-03-01
影响因子：
14.2
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
--
作者：
Tsuda, Takeshi;Nishide, Masayuki;Kumanogoh, Atsushi
背景：嗜酸性粒细胞性慢性鼻窦炎（ECRS）是慢性鼻窦炎的一种亚型。ECRS疾病活动的临床标志物和治疗策略尚未充分建立。Semaphorins 4D（semaphorin 4D，SEMA4D）是一种神经导向因子，在免疫调节和炎症性疾病中发挥重要作用。目的：探讨SEMA4D在鼻内窥镜鼻窦炎（ECRS）中的病理作用和治疗潜力。分别采用流式细胞术和免疫组化法检测鼻息肉组织和血细胞中SEMA4D的表达。在基质金属蛋白酶处理的嗜酸性粒细胞中评价可溶性SEMA4D的产生。用重组SEMA4D刺激内皮细胞，然后进行嗜酸性粒细胞跨内皮迁移测定。用曲霉蛋白酶和卵白蛋白诱导小鼠变应性慢性鼻窦炎。结果：ECRS患者血清可溶性SEMA4D水平升高，且与疾病严重程度呈正相关。ECRS患者鼻息肉组织中浸润的嗜酸性粒细胞被抗SEMA4D抗体强染色。ECRS患者的嗜酸性粒细胞表面SEMA4D表达减少，这是由于基质金属蛋白酶9介导的SEMA4D膜裂解。可溶性SEMA4D诱导嗜酸性粒细胞跨内皮迁移。在ECRS动物模型中，用抗SEMA4D抗体治疗可改善窦组织和鼻灌洗液中的嗜酸性粒细胞浸润。血清SEMA4D水平反映疾病的严重程度，抗SEMA4D抗体具有治疗ECRS的治疗潜力。
Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases.Objective: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS.Methods: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis.Results: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model.Conclusions: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.