Immunomodulatory Effects Mediated by Serotonin

Overview

Journal J Immunol Res

Publisher Wiley

Specialty Allergy & Immunology

Date 2015 May 12

PMID 25961058

Citations 79

Authors

Rodrigo Arreola

Enrique Becerril-Villanueva

Carlos Cruz-Fuentes

Marco Antonio Velasco-Velazquez

Maria Eugenia Garces-Alvarez

Gabriela Hurtado-Alvarado

Saray Quintero-Fabian

Lenin Pavon

Affiliations

Soon will be listed here.

Abstract

Serotonin (5-HT) induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a) membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b) downstream signaling transduction proteins; and (c) enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

Citing Articles

Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.

Shin H, Bang Y Immune Netw. 2025; 25(1):e10.

PMID: 40078785 PMC: 11896664. DOI: 10.4110/in.2025.25.e10.

Comprehensive view of suicide: A neuro-immune-endocrine approach.

Ponce-Regalado M, Becerril-Villanueva E, Maldonado-Garcia J, Moreno-Lafont M, Martinez-Ramirez G, Jacinto-Gutierrez S World J Psychiatry. 2025; 15(2):98484.

PMID: 39974471 PMC: 11758041. DOI: 10.5498/wjp.v15.i2.98484.

Serotonin reuptake inhibitors improve muscle stem cell function and muscle regeneration in male mice.

Fefeu M, Blatzer M, Kneppers A, Briand D, Rocheteau P, Haroche A Nat Commun. 2024; 15(1):6457.

PMID: 39085209 PMC: 11291725. DOI: 10.1038/s41467-024-50220-4.

Profound Properties of Protein-Rich, Platelet-Rich Plasma Matrices as Novel, Multi-Purpose Biological Platforms in Tissue Repair, Regeneration, and Wound Healing.

Everts P, Lana J, Alexander R, Dallo I, Kon E, Ambach M Int J Mol Sci. 2024; 25(14).

PMID: 39063156 PMC: 11277244. DOI: 10.3390/ijms25147914.

Role of Serotonergic System in Regulating Brain Tumor-Associated Neuroinflammatory Responses.

Karmakar S, Lal G Methods Mol Biol. 2024; 2761:181-207.

PMID: 38427238 DOI: 10.1007/978-1-0716-3662-6_14.

References

Finocchiaro L, Nahmod V, Launay J . Melatonin biosynthesis and metabolism in peripheral blood mononuclear leucocytes. Biochem J. 1991; 280 ( Pt 3):727-31. PMC: 1130514. DOI: 10.1042/bj2800727. View

Li N, Ghia J, Wang H, McClemens J, Cote F, Suehiro Y . Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol. 2011; 178(2):662-71. PMC: 3069907. DOI: 10.1016/j.ajpath.2010.10.028. View

Fiebich B, Akundi R, Lieb K, Candelario-Jalil E, Gmeiner D, Haus U . Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes. Scand J Rheumatol Suppl. 2004; 119:28-32. View

Hsu Sf , OConnell P, Klyachko V, Badminton M, Thomson A, Jackson M . Fundamental Ca2+ signaling mechanisms in mouse dendritic cells: CRAC is the major Ca2+ entry pathway. J Immunol. 2001; 166(10):6126-33. DOI: 10.4049/jimmunol.166.10.6126. View

ERSPAMER V, ASERO B . Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature. 1952; 169(4306):800-1. DOI: 10.1038/169800b0. View

Hellstrand K, HERMODSSON S . Enhancement of human natural killer cell cytotoxicity by serotonin: role of non-T/CD16+ NK cells, accessory monocytes, and 5-HT1A receptors. Cell Immunol. 1990; 127(1):199-214. DOI: 10.1016/0008-8749(90)90125-b. View

Arendt Nielsen L, Henriksson K . Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition. Best Pract Res Clin Rheumatol. 2007; 21(3):465-80. DOI: 10.1016/j.berh.2007.03.007. View

Sun H, Hu X, Moradel E, Weight F, Zhang L . Modulation of 5-HT3 receptor-mediated response and trafficking by activation of protein kinase C. J Biol Chem. 2003; 278(36):34150-7. DOI: 10.1074/jbc.M303584200. View

Bellizzi A, Mangia A, Chiriatti A, Petroni S, Quaranta M, Schittulli F . RhoA protein expression in primary breast cancers and matched lymphocytes is associated with progression of the disease. Int J Mol Med. 2008; 22(1):25-31. View

10.

van Panhuys N, Prout M, Forbes E, Min B, Paul W, Le Gros G . Basophils are the major producers of IL-4 during primary helminth infection. J Immunol. 2011; 186(5):2719-28. PMC: 3488853. DOI: 10.4049/jimmunol.1000940. View

11.

Meredith E, Holder M, Chamba A, Challa A, Drake-Lee A, Bunce C . The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics. FASEB J. 2005; 19(9):1187-9. DOI: 10.1096/fj.04-3477fje. View

12.

Sakowski S, Geddes T, Thomas D, Levi E, Hatfield J, Kuhn D . Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies. Brain Res. 2006; 1085(1):11-8. DOI: 10.1016/j.brainres.2006.02.047. View

13.

Mostafavi Abdolmaleky H, Faraone S, Glatt S, Tsuang M . Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res. 2004; 67(1):53-62. DOI: 10.1016/s0920-9964(03)00183-x. View

14.

Mayo J, Sainz R, Tan D, Hardeland R, Leon J, Rodriguez C . Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol. 2005; 165(1-2):139-49. DOI: 10.1016/j.jneuroim.2005.05.002. View

15.

Rinaldi A, Chiaravalli A, Mian M, Zucca E, Tibiletti M, Capella C . Serotonin receptor 3A expression in normal and neoplastic B cells. Pathobiology. 2010; 77(3):129-35. DOI: 10.1159/000292646. View

16.

Idzko M, Panther E, Stratz C, Muller T, Bayer H, Zissel G . The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004; 172(10):6011-9. DOI: 10.4049/jimmunol.172.10.6011. View

17.

Pellissier L, Barthet G, Gaven F, Cassier E, Trinquet E, Pin J . G protein activation by serotonin type 4 receptor dimers: evidence that turning on two protomers is more efficient. J Biol Chem. 2011; 286(12):9985-97. PMC: 3060553. DOI: 10.1074/jbc.M110.201939. View

18.

Vecsei L, Szalardy L, Fulop F, Toldi J . Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2012; 12(1):64-82. DOI: 10.1038/nrd3793. View

19.

Urbina M, Pineda S, Pinango L, Carreira I, Lima L . [3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with major depression before and after treatment with fluoxetine. Int J Immunopharmacol. 2003; 21(10):631-46. DOI: 10.1016/s0192-0561(99)00035-1. View

20.

Fang C, Chen H, Chiang I, Chen C, Liao J, Su T . Mirtazapine inhibits tumor growth via immune response and serotonergic system. PLoS One. 2012; 7(7):e38886. PMC: 3396612. DOI: 10.1371/journal.pone.0038886. View