Eosinophil-mediated cholinergic nerve remodeling
Eosinophil-mediated cholinergic nerve remodeling
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DOI：
10.1165/rcmb.2005-0196oc
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发表时间：
2006-06-01
影响因子：
6.4
通讯作者：
Walsh, Marie-Therese
中科院分区：
文献类型：
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作者：
Durcan, Niamh;Costello, Richard W.;Walsh, Marie-Therese
据观察，在哮喘、鼻炎、嗜酸性胃肠炎和炎症性肠病等多种炎症性疾病中，嗜酸性粒细胞定位于胆碱能神经，它们还负责诱导细胞信号传导。我们假设嗜酸性粒细胞定位于胆碱能神经的结果将涉及神经重塑过程。嗜酸性粒细胞与胆碱能 IMR32 细胞共培养导致 M-2 毒蕈碱受体表达增加，这种诱导是通过嗜酸性粒细胞蛋白（包括主要碱性蛋白和神经生长因子）的粘附依赖性释放介导的。对 M2 受体启动子序列的研究表明，这种诱导是在基因编码区上游 145 kb 的转录起始位点开始的。该启动子位点包含多种转录因子的结合位点，包括 SP1、AP1 和 AP2。嗜酸性粒细胞还诱导参与乙酰胆碱合成、储存和代谢的几种胆碱能基因的表达，包括胆碱乙酰转移酶、囊泡乙酰胆碱转移酶和乙酰胆碱酯酶。观察到的嗜酸性粒细胞诱导的酶含量变化与细胞内神经乙酰胆碱的减少但胆碱含量的增加有关，表明乙酰胆碱周转增加和乙酰胆碱酯酶活性降低，进而表明乙酰胆碱的分解代谢减少。这些数据共同表明，嗜酸性粒细胞定位于胆碱能神经会诱导神经重塑，促进胆碱能表型。
Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M-2 muscarinic receptor, with this induction being mediated via an ad hesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.