S. Typhimurium challenge in juvenile pigs modulates the expression and localization of enteric cholinergic proteins and correlates with mucosal injury and inflammation.
S. Typhimurium challenge in juvenile pigs modulates the expression and localization of enteric cholinergic proteins and correlates with mucosal injury and inflammation.
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DOI：
10.1016/j.autneu.2018.05.009
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Moeser AJ
中科院分区：
文献类型：
--
作者：
Pohl CS;Lennon EM;Li Y;DeWilde MP;Moeser AJ
胆碱能系统在调节关键的胃肠道功能，包括运动、分泌、屏障和免疫功能中起着核心作用。在急性非感染性胃肠道损伤的啮齿动物模型中，胆碱能系统起到抑制炎症的作用;然而，在炎症期间，胆碱能系统的局部表达和调节并不为人所知，特别是在感染性肠炎期间。本研究的目的是确定猪回肠中肠胆碱能系统的内在表达后，急性攻击与沙门氏菌血清型鼠伤寒沙门氏菌DT 104（S。鼠伤寒沙门氏菌）。在2天后的挑战，回肠乙酰胆碱（ACh）水平的三倍减少，观察到在挑战的动物，与对照组相比。回肠乙酰胆碱酯酶（AChE）活性降低（4倍），而胆碱乙酰转移酶（ChAT）的表达增加，在回肠和肠系膜淋巴结。ChAT的升高被发现优先定位于粘膜覆盖淋巴滤泡的派尔集合淋巴结在挑战的猪，与更强烈的标记ChAT在S。与对照组相比，鼠伤寒沙门氏菌攻毒猪。回肠毒蕈碱受体1和3的mRNA基因表达也增加了挑战猪，而毒蕈碱受体2和烟碱受体α 7亚基基因表达不受影响。ChAT蛋白表达在回肠，直肠温度和组织病理学严重程度之间呈正相关。这些数据表明S.鼠伤寒杆菌攻击通过下调乙酰胆碱浓度和乙酰胆碱降解酶同时增加乙酰胆碱合成蛋白和受体改变肠胆碱能表达。鉴于已知的胆碱能系统的抗炎作用，胆碱能基因的不同表达可能代表了在低配体可用性的情况下通过保留胆碱能信号传导来限制组织损伤的尝试。鼠伤寒沙门氏菌攻击和入侵触发免疫细胞募集、炎症和粘膜损伤，包括上皮细胞损失。随后粘膜中乙酰胆碱（ACh）浓度的降低可通过以下方式诱导代偿性反应以保存和（或）放大胆碱能信号：（1）通过上皮细胞、固有层单核细胞和肠神经元中的胆碱乙酰转移酶（ChAT）上调ACh合成（未显示）（2）通过抑制乙酰胆碱酯酶（AChE）下调ACh降解，（3）通过增加毒蕈碱M1和M3胆碱能受体的表达增强ACh信号传导。虚线表示粘膜损伤和炎症可能驱动胆碱能表达改变的假设机制。
The cholinergic system plays a central role in regulating critical gastrointestinal functions, including motility, secretion, barrier and immune function. In rodent models of acute, non-infectious gastrointestinal injury, the cholinergic system functions to inhibit inflammation; however, during inflammation local expression and regulation of the cholinergic system is not well known, particularly during infectious enteritis. The objective of this study was to determine the intrinsic expression of the enteric cholinergic system in pig ileum following an acute challenge with Salmonella enterica serovar Typhimurium DT104 (S. Typhimurium). At 2 d post-challenge, a three-fold reduction in ileal acetylcholine (ACh) levels was observed in challenged animals, compared with controls. Ileal acetylcholinesterase (AChE) activity was decreased (by four-fold) while choline acetyltransferase (ChAT) expression was increased in both the ileum and mesenteric lymph nodes. Elevated ChAT found to localize preferentially to mucosa overlying lymphoid follicles of the Peyers patch in challenged pigs, with more intense labeling for ChAT in S. Typhimurium challenged pigs compared to controls. Ileal mRNA gene expression of muscarinic receptor 1 and 3 was also increased in challenged pigs, while muscarinic receptor 2 and the nicotinic receptor alpha 7 subunit gene expression were unaffected. A positive correlation was observed between ChAT protein expression in the ileum, rectal temperature, and histopathological severity in challenged animals. These data show that inflammation from S. Typhimurium challenge alters enteric cholinergic expression by down-regulating acetylcholine concentration and acetylcholine degrading enzymes while increasing acetylcholine synthesis proteins and receptors. Given the known anti-inflammatory role of the cholinergic system, the divergent expression of cholinergic genes may represent an attempt to limit tissue damage by preserving cholinergic signaling in the face of low ligand availability. Salmonella Typhimurium challenge and invasion triggers immune cell recruitment, inflammation and mucosal injury including epithelial cell loss. Subsequent reduction in acetylcholine (ACh) concentrations in the mucosa may induce a compensatory response to preserve and (or) amplify cholinergic signaling by (1) upregulating ACh synthesis via choline acetyltransferase (ChAT) in epithelial cells, lamina propria monocytes and enteric neurons (not shown) (2) down-regulating ACh degradation via suppression of acetylcholinesterase (AChE), and (3) enhancing of ACh signaling via increased expression of muscarinic M1 and M3 cholinergic receptors. Dotted lines indicate hypothesized mechanisms by which mucosal damage and inflammation may drive altered cholinergic expression.
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DOI：
10.1038/nrd4295
发表时间：
2014-07
期刊：
Nature reviews. Drug discovery
影响因子：
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