Neuro-immune Crosstalk in the Enteric Nervous System from Early Postnatal Development to Adulthood

Abstract

SummaryCorrect development and maturation of the enteric nervous system (ENS) is critical for survival. Early in life, the ENS requires significant refinement in order to adapt to the evolving needs of the tissue, changing from milk to solid food at the time of weaning. Here, we demonstrate that resident macrophages of the muscularis externa, MMϕ, refine the ENS early in life by pruning synapses and phagocytosing abundant enteric neurons. After weaning, MMϕ continue to closely interact with the ENS, acquire a microglia-like phenotype and are crucial for the survival of enteric neurons. Of note, this microglia-like phenotype is instructed by TGFβ produced by the ENS, introducing a novel reciprocal cell-cell communication responsible for the maintenance of the neuron-associated MMФ niche in the gut. These findings elucidate a novel role of intestinal macrophages in ENS refinement early in life, and open new opportunities to treat intestinal neurodegenerative disorders by manipulating the ENS-macrophage niche.

Macrophages in the gut: Masters in multitasking

“…In the mucosa, macrophage-derived insulin-like growth factor 1 (IGF-1) is critical for mucosal microvascular development early in life, and protects the neonatal intestine during necrotizing enterocolitis, suggesting that macrophages first support endothelial sprouting early in life, while then switching to a role of endothelial support in adult life (De Schepper et al, 2019;Honda et al, 2020;Yan et al, 2022). Similarly, in the muscularis externa, we recently described a maturation switch in which muscularis macrophages are responsible for the refinement of the developing ENS during postnatal development, while then adopting to a neuro-supportive function in adulthood, a functional transition that is accompanied by significant transcriptional shifts (manuscript under peer-review; (Francesca et al, 2022)). While the factors triggering such developmental (re)programming remain to elucidated, more effort should be invested in defining how macrophages may contribute to the correct organization and development of the neonatal intestine, and define how perturbations of such perinatal macrophage functions may impact intestinal function and disease in adulthood.…”