Heck Sebastian, Daubeuf François, Le Duc Dung, Sester Martina, Bonnet Dominique, Bals Robert, Frossard Nelly, Dinh Quoc Thai
Department of Experimental Pneumology and Allergology, Internal Medicine V, Faculty of Medicine, Saarland University, Homburg, Germany.
Laboratoire d'Innovation Thérapeutique, UMR 7200, and Laboratory of Excellence Medalis, Faculté de Pharmacie, CNRS/Université de Strasbourg, Illkirch, France.
Neuroimmunomodulation. 2017;24(6):331-340. doi: 10.1159/000487140. Epub 2018 Apr 20.
The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation.
A 21-day ovalbumin (OVA)-induced allergic-airway TH2 inflammation model in BALB/c mice was used. Four groups were sensitized with OVA adsorbed on alum and challenged either with OVA or saline for 4 days. Mice were treated intranasally with chalcone 4 (300 nmol/kg body weight) or solvent 2 h before each OVA or saline challenge; 24 h after the last challenge, CD11c+F4/80- DCs were counted in the bronchoalveolar lavage. Jugular-nodose ganglion complex (JNC) sections were sampled, and for immunofluorescence staining, cryocut sections were prepared. MHC II+F4/80- DCs as well as calcitonin gene-related peptide (CGRP)- and substance P (SP)-positive neuronal cell bodies were analyzed.
In OVA-challenged mice, chalcone 4 caused a significantly decreased DC/neuron ratio in the JNC from 51.7% in solvent-treated to 32.6% in chalcone 4-treated mice. In parallel, chalcone 4 also decreased the DC population in BALF from 11.5 × 103 cells in solvent to 4.5 × 103 cells in chalcone 4-treated mice. By contrast, chalcone 4 had no effect on the expression of the neuropeptides CGRP and SP in JNC.
This study reported the CXCL12 neutraligand chalcone 4 to affect DC infiltration into the airways and airway ganglia as well as to decrease airway eosinophilic inflammation and, therefore, validated CXCL12 as a new target in allergic disease models of asthma.
据报道，趋化因子CXCL12与CXC受体4（CXCR4）相互作用在支气管哮喘的发生和发展中起作用，但其作用机制尚不清楚。本研究的目的是评估CXCL12中性配体查耳酮4在小鼠过敏性气道炎症模型中对树突状细胞（DCs）迁移的影响。
采用21天卵清蛋白（OVA）诱导的BALB/c小鼠过敏性气道TH2炎症模型。四组用吸附在明矾上的OVA致敏，并用OVA或生理盐水攻击4天。在每次OVA或生理盐水攻击前2小时，给小鼠鼻内注射查耳酮4（300 nmol/kg体重）或溶剂；最后一次攻击后24小时，对支气管肺泡灌洗中的CD11c+F4/80-DCs进行计数。采集颈-结神经节复合体（JNC）切片，制备用于免疫荧光染色的冷冻切片。分析MHC II+F4/80-DCs以及降钙素基因相关肽（CGRP）和P物质（SP）阳性神经元细胞体。
在OVA攻击的小鼠中，查耳酮4使JNC中的DC/神经元比率显著降低，从溶剂处理组的51.7%降至查耳酮4处理组的32.6%。同时，查耳酮4也使BALF中的DC数量从溶剂处理组的11.5×103个细胞降至查耳酮4处理组的4.5×103个细胞。相比之下，查耳酮4对JNC中神经肽CGRP和SP的表达没有影响。
本研究报道了CXCL12中性配体查耳酮4可影响DC向气道和气道神经节的浸润，并减少气道嗜酸性炎症，因此，验证了CXCL12作为哮喘过敏性疾病模型中的一个新靶点。
