嗜酸粒细胞衍生信号素 4D 在嗜酸粒细胞性慢性鼻-鼻窦炎中的病理和治疗意义。
Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.
机构信息
Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan.
Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan.
出版信息
J Allergy Clin Immunol. 2020 Mar;145(3):843-854.e4. doi: 10.1016/j.jaci.2019.12.893. Epub 2020 Feb 5.
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.
背景
嗜酸性慢性鼻-鼻窦炎（ECRS）是慢性鼻-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得到充分确立。尽管信号素最初被鉴定为神经元导向因子，但越来越明显的是，它们在免疫调节和炎症性疾病中发挥着关键作用。
目的
我们旨在研究信号素 4D（SEMA4D）在 ECRS 中的病理功能和治疗潜力。
方法
通过 ELISA 测量鼻窦疾病患者的血清可溶性 SEMA4D 水平。通过流式细胞术和免疫组织化学分别评估血液细胞和鼻息肉组织中 SEMA4D 的表达。通过基质金属蛋白酶处理嗜酸性粒细胞评估可溶性 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实验。使用曲霉菌蛋白酶和卵清蛋白在小鼠中诱导变应性慢性鼻-鼻窦炎。通过组织学和鼻洗液分析评估抗 SEMA4D 抗体治疗的效果。
结果
ECRS 患者的血清可溶性 SEMA4D 水平升高，并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与抗 SEMA4D 抗体强烈染色。ECRS 患者嗜酸性粒细胞表面 SEMA4D 的表达减少，这是由于基质金属蛋白酶-9 介导的细胞膜 SEMA4D 的裂解。可溶性 SEMA4D 诱导嗜酸性粒细胞跨内皮迁移。用抗 SEMA4D 抗体治疗可改善 ECRS 动物模型中鼻窦组织和鼻洗液中的嗜酸性粒细胞浸润。
结论
嗜酸性粒细胞衍生的 SEMA4D 加重 ECRS。血清 SEMA4D 水平反映疾病严重程度，抗 SEMA4D 抗体作为 ECRS 的治疗方法具有治疗潜力。
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