Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain.
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom.
J Cell Physiol. 2018 May;233(5):4183-4193. doi: 10.1002/jcp.26229. Epub 2017 Dec 29.
Serotonin (5-HT) is an essential gastrointestinal modulator whose effects regulate the intestinal physiology. 5-HT effects depend on extracellular 5-HT bioavailability, which is controlled by the serotonin transporter (SERT) expressed in both the apical and basolateral membranes of enterocytes. SERT is a critical target for regulating 5-HT levels and consequently, modulating the intestinal physiology. The deregulation of innate immune receptors has been extensively studied in inflammatory bowel diseases (IBD), where an exacerbated defense response to commensal microbiota is observed. Interestingly, many innate immune receptors seem to affect the serotonergic system, demonstrating a new way in which microbiota could modulate the intestinal physiology. Therefore, our aim was to analyze the effects of NOD1 activation on SERT function, as well as NOD1's interaction with other immune receptors such as TLR2 and TLR4. Our results showed that NOD1 activation inhibits SERT activity and expression in Caco-2/TC7 cells through the extracellular signal-regulated kinase (ERK) signaling pathway. A negative feedback between 5-HT and NOD1 expression was also described. The results showed that TLR2 and TLR4 activation seems to regulate NOD1 expression in Caco-2/TC7 cells. To assess the extend of cross-talk between NOD1 and TLRs, NOD1 expression was measured in the intestinal tract (ileum and colon) of wild type mice and mice with individual knockouts of TLR2, and TLR4 as well as double knockout TLR2/TLR4 mice. Hence, we demonstrate that NOD1 acts on the serotonergic system decreasing SERT activity and molecular expression. Additionally, NOD1 expression seems to be modulated by 5-HT and other immune receptors as TLR2 and TLR4. This study could clarify the relation between both the intestinal serotonergic system and innate immune system, and their implications in intestinal inflammation.
血清素（5-HT）是一种重要的胃肠调节剂，其作用调节肠道生理。5-HT 的作用取决于细胞外 5-HT 的生物利用度，这由肠上皮细胞的顶膜和基底外侧膜表达的血清素转运体（SERT）控制。SERT 是调节 5-HT 水平并因此调节肠道生理的关键靶标。固有免疫受体的失调在炎症性肠病（IBD）中得到了广泛研究，其中观察到对共生微生物群落的防御反应过度。有趣的是，许多固有免疫受体似乎影响 5-羟色胺能系统，展示了微生物群落调节肠道生理的新途径。因此，我们的目的是分析 NOD1 激活对 SERT 功能的影响，以及 NOD1 与其他免疫受体（如 TLR2 和 TLR4）的相互作用。我们的结果表明，NOD1 激活通过细胞外信号调节激酶（ERK）信号通路抑制 Caco-2/TC7 细胞中的 SERT 活性和表达。还描述了 5-HT 和 NOD1 表达之间的负反馈。结果表明，TLR2 和 TLR4 的激活似乎调节 Caco-2/TC7 细胞中的 NOD1 表达。为了评估 NOD1 和 TLR 之间的串扰程度，在野生型小鼠和 TLR2、TLR4 单个敲除以及 TLR2/TLR4 双敲除小鼠的回肠和结肠中测量了 NOD1 表达。因此，我们证明 NOD1 作用于 5-羟色胺能系统，降低 SERT 活性和分子表达。此外，NOD1 表达似乎受到 5-HT 和其他免疫受体（如 TLR2 和 TLR4）的调节。这项研究可以阐明肠道 5-羟色胺能系统和固有免疫系统之间的关系及其在肠道炎症中的意义。
