Cell
Volume 184, Issue 23, 11 November 2021, Pages 5715-5727.e12
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Article
Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections

https://doi.org/10.1016/j.cell.2021.10.004Get rights and content
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Highlights

  • Bacteria-induced neuroprotection is mediated by β-2AR signaling in macrophages

  • Helminth-induced neuroprotection relies on eosinophil-derived IL-4 and IL-13

  • Pet store mice display similar neuroprotection as previously infected SPF mice

  • Post-infectious bone marrow and tissue environment maintain long-term neuroprotection

Summary

The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss, dysmotility, and maintains energy balance during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via β2-adrenergic receptors (β2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and IL-13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease or tissue tolerance that preserves ENS number and functionality.

Keywords

neuroimmunology
macrophages
eosinophils
enteric infections
small intestine
enteric neurons

Data and code availability

  • RNA-seq data have been deposited at GEO and are publicly available as of the date of publication. Accession number is listed in the Key Resources Table.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

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Present address: Laboratory of Development and Homeostasis of the Nervous System, The Francis Crick Institute, London, UK

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Lead contact