致死性哮喘中的神经可塑性和神经免疫相互作用
2024/11/29
摘要
研究背景：气道神经元功能和密度的改变以及免疫细胞和周围感觉神经之间的双向相互作用被认为是引发和维持炎症的原因，而炎症与哮喘严重程度有关。迄今为止，很少有研究分析哮喘个体组织中的神经可塑性和神经炎症。我们假设这些现象的存在是致死性哮喘的病理特征。
方法：我们定量分析了泛神经元标志物PGP9.5和神经元感觉源性神经肽降钙素基因相关肽（CGRP）在12例因哮喘发作死亡的患者的大气道中的表达，并与10例对照肺样本进行了比较。定量分析神经束与嗜酸性粒细胞、肥大细胞和CADM1阳性细胞的邻近程度。此外，我们还开发了一个hPSC衍生的感觉神经元/肥大细胞共培养模型，从中纯化肥大细胞并评估基因表达谱的差异。
结果：致死性哮喘患者气道中PGP9.5和CGRP阳性面积增加，提示感觉神经可塑性。嗜酸性粒细胞、肥大细胞和CADM1+细胞密切接触或接触气道神经束，且在致死性哮喘样本中显著增高。体外共培养模型显示，人类肥大细胞与感觉神经元黏附并形成了独特的基因表达谱，其特征是与异性黏附、活化和分化标志物相关的基因表达上调，如CADM4， PTGS2, C-KIT, GATA2， HDC, CPA3， ATXN1和VCAM1。
结论：我们的研究结果支持神经可塑性和神经免疫相互作用在致死性哮喘中发挥重要作用，这可能与致死性哮喘发作的严重程度有关。因此，神经元和肥大细胞相互作用的存在导致了细胞类型的差异基因表达谱。
Guilherme Dragunas, Carli S Koster, Natalia de Souza Xavier Costa, Barbro N Melgert, Carolina D Munhoz, Reinoud Gosens, Thais Mauad
Abstract
Background: Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma.
Methods: We have quantified the expression of the pan-neuronal marker PGP9.5 and the neuronal sensory-derived neuropeptide calcitonin gene-related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC-derived sensory neuron/mast cell co-culture model, from where mast cells were purified and differences in gene expression profile assessed.
Results: Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. In vitro co-culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C-KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1.
Conclusions: Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type.
研究背景：气道神经元功能和密度的改变以及免疫细胞和周围感觉神经之间的双向相互作用被认为是引发和维持炎症的原因，而炎症与哮喘严重程度有关。迄今为止，很少有研究分析哮喘个体组织中的神经可塑性和神经炎症。我们假设这些现象的存在是致死性哮喘的病理特征。
方法：我们定量分析了泛神经元标志物PGP9.5和神经元感觉源性神经肽降钙素基因相关肽（CGRP）在12例因哮喘发作死亡的患者的大气道中的表达，并与10例对照肺样本进行了比较。定量分析神经束与嗜酸性粒细胞、肥大细胞和CADM1阳性细胞的邻近程度。此外，我们还开发了一个hPSC衍生的感觉神经元/肥大细胞共培养模型，从中纯化肥大细胞并评估基因表达谱的差异。
结果：致死性哮喘患者气道中PGP9.5和CGRP阳性面积增加，提示感觉神经可塑性。嗜酸性粒细胞、肥大细胞和CADM1+细胞密切接触或接触气道神经束，且在致死性哮喘样本中显著增高。体外共培养模型显示，人类肥大细胞与感觉神经元黏附并形成了独特的基因表达谱，其特征是与异性黏附、活化和分化标志物相关的基因表达上调，如CADM4， PTGS2, C-KIT, GATA2， HDC, CPA3， ATXN1和VCAM1。
结论：我们的研究结果支持神经可塑性和神经免疫相互作用在致死性哮喘中发挥重要作用，这可能与致死性哮喘发作的严重程度有关。因此，神经元和肥大细胞相互作用的存在导致了细胞类型的差异基因表达谱。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Allergy. 2024 Nov 1. doi: 10.1111/all.16373.)
Neuroplasticity and neuroimmune interactions in fatal asthma(Allergy. 2024 Nov 1. doi: 10.1111/all.16373.)
Guilherme Dragunas, Carli S Koster, Natalia de Souza Xavier Costa, Barbro N Melgert, Carolina D Munhoz, Reinoud Gosens, Thais Mauad
Abstract
Background: Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma.
Methods: We have quantified the expression of the pan-neuronal marker PGP9.5 and the neuronal sensory-derived neuropeptide calcitonin gene-related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC-derived sensory neuron/mast cell co-culture model, from where mast cells were purified and differences in gene expression profile assessed.
Results: Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. In vitro co-culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C-KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1.
Conclusions: Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type.
上一篇：
哮喘-慢性阻塞性肺疾病重叠和嗜酸性粒细胞慢性阻塞性肺疾病中嗜酸性粒细胞的炎症特征：一项多组学研究
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线粒体DNA拷贝数变异与哮喘风险、严重程度和急性发作的相关性分析
