Intestinal Serotonergic System is Modulated by Toll-like Receptor 9

Overview

Journal J Physiol Biochem

Specialties Biochemistry
Physiology

Date 2022 Jun 7

PMID 35670957

Authors

Elena Layunta

Eva Latorre

Laura Grasa

Maria Pilar Arruebo

Berta Buey

Ana I Alcalde

Jose E Mesonero

Affiliations

Soon will be listed here.

Abstract

Intestinal serotonergic system is a key modulator of intestinal homeostasis; however, its regulation is still unclear. Toll-like receptor 9 (TLR9), an innate immune receptor, detects different external agents in the intestine, preserving intestinal integrity. Since little is known about TLR9 role in the intestine, our aim was to address the potential regulation between TLR9 and intestinal serotonergic system. Caco-2/TC7 cell line and intestinal tract of Tlr9 mice were used in this study. Serotonin uptake studies were performed, and molecular expression of different serotonergic components was analyzed by western blot and real-time PCR. Our results show that TLR9 activation inhibits serotonin transporter activity and expression, involving p38/MAPK and ERK/MAPK intracellular pathways, and reciprocally, serotonin increases TLR9 expression. Supporting this interaction, serotonin transporter, serotonin receptors and serotonin producer enzymes were found altered in intestinal tract of Tlr9 mice. We conclude that TLR9 could contribute to intestinal homeostasis by modulation of intestinal serotonergic system.

Citing Articles

Gut Microbiota-Derived Short-Chain Fatty Acids: Novel Regulators of Intestinal Serotonin Transporter.

Buey B, Forcen A, Grasa L, Layunta E, Mesonero J, Latorre E Life (Basel). 2023; 13(5).

PMID: 37240731 PMC: 10221112. DOI: 10.3390/life13051085.

References

Huang X, Yang Y . Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert Opin Ther Targets. 2010; 14(8):787-96. PMC: 2917181. DOI: 10.1517/14728222.2010.501333. View

Volpi C, Fallarino F, Pallotta M, Bianchi R, Vacca C, Belladonna M . High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway. Nat Commun. 2013; 4:1852. DOI: 10.1038/ncomms2874. View

Mendoza C, Matheus N, Latorre E, Castro M, Mesonero J, Alcalde A . Toll-like receptor 3 activation affects serotonin transporter activity and expression in human enterocyte-like Caco-2 cells. Cell Physiol Biochem. 2012; 30(1):187-98. DOI: 10.1159/000339057. View

Greenbaum D, Colangelo C, Williams K, Gerstein M . Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol. 2003; 4(9):117. PMC: 193646. DOI: 10.1186/gb-2003-4-9-117. View

Zarember K, Godowski P . Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002; 168(2):554-61. DOI: 10.4049/jimmunol.168.2.554. View

Hug H, Mohajeri M, La Fata G . Toll-Like Receptors: Regulators of the Immune Response in the Human Gut. Nutrients. 2018; 10(2). PMC: 5852779. DOI: 10.3390/nu10020203. View

Lee J, Mo J, Katakura K, Alkalay I, Rucker A, Liu Y . Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol. 2006; 8(12):1327-36. DOI: 10.1038/ncb1500. View

Mukherjee S, Karmakar S, Sinha Babu S . TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis. 2016; 20(2):193-204. PMC: 9427569. DOI: 10.1016/j.bjid.2015.10.011. View

Spiller R, Major G . IBS and IBD - separate entities or on a spectrum?. Nat Rev Gastroenterol Hepatol. 2016; 13(10):613-21. DOI: 10.1038/nrgastro.2016.141. View

10.

Layunta E, Buey B, Mesonero J, Latorre E . Crosstalk Between Intestinal Serotonergic System and Pattern Recognition Receptors on the Microbiota-Gut-Brain Axis. Front Endocrinol (Lausanne). 2021; 12:748254. PMC: 8607755. DOI: 10.3389/fendo.2021.748254. View

11.

Gu X, Wu G, Yao Y, Zeng J, Shi D, Lv T . Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway. Free Radic Biol Med. 2015; 83:149-58. DOI: 10.1016/j.freeradbiomed.2015.02.034. View

12.

Iceta R, Mesonero J, Aramayona J, Alcalde A . Expression of 5-HT1A and 5-HT7 receptors in Caco-2 cells and their role in the regulation of serotonin transporter activity. J Physiol Pharmacol. 2009; 60(1):157-64. View

13.

Huang W, Zhao Y, Zhu X, Cai Z, Wang S, Yao S . Fluoxetine upregulates phosphorylated-AKT and phosphorylated-ERK1/2 proteins in neural stem cells: evidence for a crosstalk between AKT and ERK1/2 pathways. J Mol Neurosci. 2012; 49(2):244-9. DOI: 10.1007/s12031-012-9822-5. View

14.

Rose 2nd W, Sakamoto K, Leifer C . TLR9 is important for protection against intestinal damage and for intestinal repair. Sci Rep. 2012; 2:574. PMC: 3418518. DOI: 10.1038/srep00574. View

15.

Mousavizadeh K, Rahimian R, Fakhfouri G, Aslani F, Ghafourifar P . Anti-inflammatory effects of 5-HT receptor antagonist, tropisetron on experimental colitis in rats. Eur J Clin Invest. 2009; 39(5):375-83. DOI: 10.1111/j.1365-2362.2009.02102.x. View

16.

Yu S, Gao N . Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance. Cell Mol Life Sci. 2015; 72(17):3343-53. PMC: 4534336. DOI: 10.1007/s00018-015-1931-1. View

17.

Dotan I, Levy-Nissenbaum E, Chowers Y, Fich A, Israeli E, Adar T . Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial. Dig Dis Sci. 2016; 61(11):3246-3254. DOI: 10.1007/s10620-016-4276-1. View

18.

Okamoto T, Barton M, Hennig G, Birch G, Grainger N, Corrigan R . Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil. 2014; 26(4):556-70. DOI: 10.1111/nmo.12302. View

19.

Williams B, Van Benschoten A, Cimermancic P, Donia M, Zimmermann M, Taketani M . Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014; 16(4):495-503. PMC: 4260654. DOI: 10.1016/j.chom.2014.09.001. View

20.

Wentworth C, Jones R, Kwon Y, Nusrat A, Neish A . Commensal-epithelial signaling mediated via formyl peptide receptors. Am J Pathol. 2010; 177(6):2782-90. PMC: 2993286. DOI: 10.2353/ajpath.2010.100529. View