Dedicated macrophages organize and maintain the enteric nervous system

Abstract

Correct 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 ENSmacrophage niche.

Inflammation‐Responsive Cell Membrane‐Camouflaged Nanoparticles against Liver Fibrosis via Regulating Endoplasmic Reticulum Stress and Oxidative Stress

“…Our PCR results further validated the elevated expression level of TGFB1 (Tgfb1) in both children with CBA and in the CCL 4 ‐induced liver fibrosis mouse model (Figure S3C, Supporting Information). During hepatic stellate cell activation, TGFβ was secreted by a variety of cells, [ 23 ] such as lymphocytes, [ 24 ] mesenchymal stromal cells, [ 25 ] and so on. Given that hepatic parenchymal cells are the predominant cells in the liver, [ 26 ] they likely play a pivotal role in secreting TGFβ1, [ 27 ] especially considering its predominant representation within the TGFβ family.…”

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

“…The latter are consistent with previous observations of conserved MHCII hi macrophage interstitial populations across tissues 41 and the high MHCII expression of myenteric macrophages 24 . Mp2 and Mp6 also highly expressed Csf1r , which is crucial for the survival and phenotype of ENS-resident macrophages 24 , and the canonical microglial gene Ctss , which is also highly expressed in nerve-associated macrophages 23 (Fig 2F). Therefore, it is highly likely that our Mp2 and Mp6 clusters represent ENS macrophages.…”

“…Moreover, although excessive synaptic pruning due to α-syn has not been shown, it is a well-studied mechanism for cognitive dysfunction in Alzheimer’s-related pathology 37, 38, 70 . Additionally, ENS macrophages engage in synaptic refinement during development 23 . Thus, to our knowledge, our findings are the first to support a role for macrophage-mediated synaptic pruning in response to neuronal α-syn pathology.…”

Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity

“…We therefore questioned whether such a transition away from a classical macrophage identity occurred in humans. Post-natal maturation of intestinal macrophages has been linked to the acquisition of immune functions (Viola et al 2023). We posited that a similar maturation process occurred in human skin after birth, and was linked to LC specification.…”