Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss

Cell. 2020 Jan 9;180(1):64-78.e16. doi: 10.1016/j.cell.2019.12.002.


Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via β2-adrenergic receptor (β2-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.

Keywords: NLRP6; adrenergic receptors; arginase 1; caspase 11; enteric infections; enteric neurons; gut macrophages; inflammasome; neuronal damage; polyamines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents
  • Animals
  • Arginase / metabolism
  • Caspases, Initiator / immunology
  • Caspases, Initiator / metabolism
  • Enteric Nervous System / immunology
  • Enteric Nervous System / metabolism
  • Female
  • Gastrointestinal Diseases
  • Gastrointestinal Microbiome
  • Infections
  • Inflammation / immunology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Intestine, Small / immunology
  • Intestines / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microbiota
  • Neurons / physiology
  • Receptors, Adrenergic, beta-2 / immunology
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism
  • Signal Transduction


  • Adrenergic Agents
  • Nod-like receptor pyrin domain-containing protein 6, mouse
  • Receptors, Adrenergic, beta-2
  • Receptors, Cell Surface
  • Casp4 protein, mouse
  • Caspases, Initiator
  • Arg1 protein, mouse
  • Arginase