NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells
| Autor: | José E. Mesonero, Marta Castro, Ana I. Alcalde, Eva Latorre, Laura Grasa, Elena Layunta, Raquel Forcén, Maykel Arias |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Physiology Nod2 Signaling Adaptor Protein 5-HT Serotonergic lcsh:Physiology lcsh:Biochemistry Mice 03 medical and health sciences Extracellular Animals Humans TLR2 lcsh:QD415-436 TLR4 Intestinal Mucosa PRRs Receptor Serotonin transporter Mice Knockout Serotonin Plasma Membrane Transport Proteins Innate immune system lcsh:QP1-981 biology SERT Toll-Like Receptor 2 digestive system diseases Intestine Cell biology Toll-Like Receptor 4 Enterocytes 030104 developmental biology biology.protein RIP2/RICK Serotonin Caco-2 Cells |
| Zdroj: | Zaguán. Repositorio Digital de la Universidad de Zaragoza instname Cellular Physiology and Biochemistry, Vol 47, Iss 3, Pp 1217-1229 (2018) |
| Popis: | Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression. |
| Databáze: | OpenAIRE |
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