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Proc Natl Acad Sci U S A. 2018 May 1;115(18):4696-4701. doi: 10.1073/pnas.1802490115. Epub 2018 Apr 17.

Muscularis macrophage development in the absence of an enteric nervous system.

Author information

1
Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104-4318.
2
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
4
Division of Rheumatology, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318.
5
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
6
Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO 63110.
7
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
8
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
9
Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104-4318; HeuckerothR@email.chop.edu.

Abstract

The nervous system of the bowel regulates the inflammatory phenotype of tissue resident muscularis macrophages (MM), and in adult mice, enteric neurons are the main local source of colony stimulating factor 1 (CSF1), a protein required for MM survival. Surprisingly, we find that during development MM colonize the bowel before enteric neurons. This calls into question the requirement for neuron-derived CSF1 for MM colonization of the bowel. To determine if intestinal innervation is required for MM development, we analyzed MM of neonatal Ret-/- (Ret KO) mice that have no enteric nervous system in small bowel or colon. We found normal numbers of well-patterned MM in Ret KO bowel. Similarly, the abundance and distribution of MM in aganglionic human colon obtained from Hirschsprung disease patients was normal. We also identify endothelial cells and interstitial cells of Cajal as the main sources of CSF1 in the developing bowel. Additionally, MM from neonatal Ret KOs do not differ from controls in baseline activation status or cytokine-production in response to lipopolysaccharide. Unexpectedly, these data demonstrate that the enteric nervous system is dispensable for MM colonization and patterning in the bowel, and suggest that modulatory interactions between MM and the bowel nervous system are established postnatally.

KEYWORDS:

Hirschsprung disease; Ret; enteric nervous system; muscularis macrophages; neuroimmunology

PMID:
29666241
PMCID:
PMC5939112
[Available on 2018-11-01]
DOI:
10.1073/pnas.1802490115

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