Mouse Enteric Neurons Control Intestinal Plasmacytoid Dendritic Cell Function Via Serotonin-HTR7 Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 25

PMID 39455564

Authors

Hailong Zhang

Yuko Hasegawa

Masataka Suzuki

Ting Zhang

Deborah R Leitner

Ruaidhri P Jackson

Matthew K Waldor

Affiliations

Soon will be listed here.

Abstract

Serotonergic neurons in the central nervous system control behavior and mood, but knowledge of the roles of serotonergic circuits in the regulation of immune homeostasis is limited. Here, we employ mouse genetics to investigate the functions of enteric serotonergic neurons in the control of immune responses and find that these circuits regulate IgA induction and boost host defense against oral, but not systemic Salmonella Typhimurium infection. Enteric serotonergic neurons promote gut-homing, retention and activation of intestinal plasmacytoid dendritic cells (pDC). Mechanistically, this neuro-immune crosstalk is achieved through a serotonin-5-HT receptor 7 (HTR7) signaling axis that ultimately facilitates the pDC-mediated differentiation of IgA B cells from IgD precursors in the gut. Single-cell RNA-seq data further reveal novel patterns of bidirectional communication between specific subsets of enteric neurons and lamina propria DC. Our findings thus reveal a close interplay between enteric serotonergic neurons and gut immune homeostasis that enhances mucosal defense.

References

Gershon M, Tamir H . Release of endogenous 5-hydroxytryptamine from resting and stimulated enteric neurons. Neuroscience. 1981; 6(11):2277-86. DOI: 10.1016/0306-4522(81)90017-8. View

Persson E, Scott C, Mowat A, Agace W . Dendritic cell subsets in the intestinal lamina propria: ontogeny and function. Eur J Immunol. 2013; 43(12):3098-107. PMC: 3933733. DOI: 10.1002/eji.201343740. View

Wang Y, Cao Y, Pan C, Zhou Z, Yang L, Lusis A . Intestinal cell type-specific communication networks underlie homeostasis and response to Western diet. J Exp Med. 2023; 220(5). PMC: 10038833. DOI: 10.1084/jem.20221437. View

Yoo B, Mazmanian S . The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. Immunity. 2017; 46(6):910-926. PMC: 5551410. DOI: 10.1016/j.immuni.2017.05.011. View

Jin S, Guerrero-Juarez C, Zhang L, Chang I, Ramos R, Kuan C . Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021; 12(1):1088. PMC: 7889871. DOI: 10.1038/s41467-021-21246-9. View

Lesch K, Araragi N, Waider J, van den Hove D, Gutknecht L . Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1601):2426-43. PMC: 3405678. DOI: 10.1098/rstb.2012.0039. View

Meng Y, Xiong T, Zhao R, Liu J, Yu G, Xiao J . Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese. Int J Infect Dis. 2020; 98:268-274. DOI: 10.1016/j.ijid.2020.06.104. View

Walther D, Peter J, Bashammakh S, Hortnagl H, Voits M, Fink H . Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003; 299(5603):76. DOI: 10.1126/science.1078197. View

Guseva D, Holst K, Kaune B, Meier M, Keubler L, Glage S . Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract. Inflamm Bowel Dis. 2014; 20(9):1516-29. DOI: 10.1097/MIB.0000000000000150. View

10.

Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M . Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity. 2011; 34(2):247-57. DOI: 10.1016/j.immuni.2011.02.002. View

11.

Morarach K, Mikhailova A, Knoflach V, Memic F, Kumar R, Li W . Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing. Nat Neurosci. 2020; 24(1):34-46. PMC: 7610403. DOI: 10.1038/s41593-020-00736-x. View

12.

Jang M, Sougawa N, Tanaka T, Hirata T, Hiroi T, Tohya K . CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J Immunol. 2006; 176(2):803-10. DOI: 10.4049/jimmunol.176.2.803. View

13.

Okaty B, Sturrock N, Escobedo Lozoya Y, Chang Y, Senft R, Lyon K . A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe neurons. Elife. 2020; 9. PMC: 7308082. DOI: 10.7554/eLife.55523. View

14.

Reboldi A, Arnon T, Rodda L, Atakilit A, Sheppard D, Cyster J . IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches. Science. 2016; 352(6287):aaf4822. PMC: 4890166. DOI: 10.1126/science.aaf4822. View

15.

Amireault P, Sibon D, Cote F . Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci. 2013; 4(1):64-71. PMC: 3547480. DOI: 10.1021/cn300154j. View

16.

Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Muller J, Zeng Y . Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol. 2006; 10(3):309-20. DOI: 10.1017/S1461145706007437. View

17.

Chu C, Artis D, Chiu I . Neuro-immune Interactions in the Tissues. Immunity. 2020; 52(3):464-474. PMC: 10710744. DOI: 10.1016/j.immuni.2020.02.017. View

18.

Salvan P, Fonseca M, Winkler A, Beauchamp A, Lerch J, Johansen-Berg H . Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks. Nat Neurosci. 2022; 26(1):53-63. PMC: 9829536. DOI: 10.1038/s41593-022-01213-3. View

19.

Gutknecht L, Waider J, Kraft S, Kriegebaum C, Holtmann B, Reif A . Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J Neural Transm (Vienna). 2008; 115(8):1127-32. DOI: 10.1007/s00702-008-0096-6. View

20.

Rodrigo Mora J, Iwata M, Eksteen B, Song S, Junt T, Senman B . Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006; 314(5802):1157-60. DOI: 10.1126/science.1132742. View