Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages

Cell. 2016 Jan 28;164(3):378-91. doi: 10.1016/j.cell.2015.12.023. Epub 2016 Jan 14.


Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / physiology
  • Intestine, Small / cytology
  • Intestine, Small / immunology
  • Intestine, Small / physiology*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Mice
  • Mucous Membrane / cytology
  • Mucous Membrane / physiology
  • Neuroimmunomodulation
  • Neurons / cytology*
  • Neurons / physiology
  • Receptors, Adrenergic, beta-2 / metabolism
  • Salmonella Infections / immunology
  • Salmonella typhimurium / physiology
  • Specific Pathogen-Free Organisms


  • Receptors, Adrenergic, beta-2