Mouse enteric neurons control intestinal plasmacytoid dendritic cell function via serotonin-HTR7 signaling

• Published in: Nature communications Vol. 15; no. 1; pp. 9237 - 13
• Main Authors: Zhang, Hailong, Hasegawa, Yuko, Suzuki, Masataka, Zhang, Ting, Leitner, Deborah R., Jackson, Ruaidhrí P., Waldor, Matthew K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 14/1; 38/1; 38/39; 631/250/254; 631/250/347; 631/378/1959/1315/1951; 631/80/86; 64; 64/60; Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell activation; Cell differentiation; Cell Differentiation - immunology; Cell interactions; Central nervous system; Circuits; Crosstalk; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic structure; Differentiation; Digestive system; Enteric nervous system; Enteric Nervous System - immunology; Enteric Nervous System - metabolism; Gastrointestinal tract; Genetics; Homeostasis; Homing; Homing behavior; Humanities and Social Sciences; Immunoglobulin A; Immunoglobulin A - immunology; Immunoglobulin A - metabolism; Immunoglobulin D; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestine; Intestines - immunology; Lamina propria; Lymphocytes B; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucosal immunity; multidisciplinary; Neurons; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Salmonella; Salmonella Infections - immunology; Salmonella Infections - metabolism; Salmonella Infections - microbiology; Salmonella typhimurium - immunology; Salmonella typhimurium - physiology; Science; Science (multidisciplinary); Serotonergic Neurons - metabolism; Serotonin; Serotonin - metabolism; Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53545-2

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. Roles of serotonergic neurons in immune homeostasis and host defense are largely unexplored. Here the authors show that in mice enteric serotonergic neurons regulate immune homeostasis and host defense against Salmonella infection by orchestrating gut homing and activation of plasmacytoid dendritic cell, ultimately promoting the differentiation of protective IgA + B cells.