BackgroundAlteration 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.MethodsWe 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.ResultsFatal 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.ConclusionsOur 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.

中文翻译：

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致命性哮喘的神经可塑性和神经免疫相互作用


背景气道神经元功能和密度的改变以及免疫细胞和感觉周围神经之间的双向相互作用已被提出以触发和延续导致哮喘严重程度的炎症。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将是致命性哮喘的病理特征。方法我们已经量化了 12 名因哮喘发作而死亡的个体的大气道中泛神经元标志物 PGP9.5 和神经元感觉衍生的神经肽降钙素基因相关肽 （CGRP） 的表达，并与 10 个对照肺样本进行了比较。还量化了神经束与嗜酸性粒细胞、肥大细胞和 CADM1 + 细胞之间的接近程度。我们还开发了一种 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 阳性区域较高，表明感觉神经可塑性。在密切接触或接触气道神经束时观察到嗜酸性粒细胞、肥大细胞和 CADM1 + 细胞，发现这在致命的哮喘样本中具有统计学意义。体外共培养模型显示，人肥大细胞粘附在感觉神经元上并产生独特的基因表达谱，其特征是与异嗜性粘附、激活和分化标志物相关的基因表达上调，例如 CADM4、PTGS2、C-KIT、GATA2、HDC、CPA3、ATXN1 和 VCAM1。结论我们的结果支持神经可塑性和神经免疫相互作用在致命性哮喘中的重要作用，这可能与致命发作的严重程度有关。 因此，物理神经元和肥大细胞相互作用的存在导致后期细胞类型中的基因表达谱差异。