Dedicated macrophages organize and maintain the enteric nervous system

• Published in: Nature (London) 2023-06, Vol.618 (7966), p.818-826
• Main Authors: Viola, Maria Francesca, Chavero-Pieres, Marta, Modave, Elodie, Delfini, Marcello, Stakenborg, Nathalie, Estévez, Maria Cuende, Fabre, Naomi, Appeltans, Iris, Martens, Tobie, Vandereyken, Katy, Theobald, Hannah, Van Herck, Jens, Petry, Philippe, Verheijden, Simon, De Schepper, Sebastiaan, Sifrim, Alejandro, Liu, Zhaoyuan, Ginhoux, Florent, Azhar, Mohamad, Schlitzer, Andreas, Matteoli, Gianluca, Kierdorf, Katrin, Prinz, Marco, Vanden Berghe, Pieter, Voet, Thierry, Boeckxstaens, Guy
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 38/32; 38/35; 38/77; 631/250/2504/342; 631/250/371; 631/378/1959; 631/378/2571; 64/110; 64/60; 82; 82/51; Cell Communication; Cell interactions; Depletion; Enteric nervous system; Enteric Nervous System - cytology; Enteric Nervous System - growth & development; Enteric Nervous System - physiology; Gastrointestinal Transit; Genotype & phenotype; Growth factors; Humanities and Social Sciences; Intestine; Intestines - innervation; Lymphotoxin-alpha - metabolism; Macrophages; Macrophages - metabolism; Macrophages - physiology; multidisciplinary; Nervous system; Neurodegeneration; Neuronal Plasticity; Neurons; Neurons - physiology; Phagocytosis; Phenotype; Phenotypes; Science; Science (multidisciplinary); Synapses; Transcriptome; Transcriptomes; Transit; Weaning
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06200-7

Correct development and maturation of the enteric nervous system (ENS) is critical for survival 1 . At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood 2 . Here we demonstrate that resident macrophages of the muscularis externa (MMϕ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMϕ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMϕ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-β produced by the ENS; depletion of the ENS and disruption of transforming growth factor-β signalling result in a decrease in neuron-associated MMϕ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell–cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche. Resident macrophages of the muscularis externa refine the enteric nervous system (ENS) early in life by pruning synapses and phagocytosing enteric neurons, and later switch to a neuro-supportive function, indicating that the ENS is governed by a dedicated population of resident macrophages that adapt to the timely needs of the ENS.