TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells

Immunity. 2018 Jul 17;49(1):107-119.e4. doi: 10.1016/j.immuni.2018.04.021. Epub 2018 Jun 26.


Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.

Keywords: COX-1; CX3CR1; E-prostanoid receptor; TRPV4; chemogenetics; gastrointestinal motility; muscularis macrophage; optogenetics; prostaglandin E2.

Publication types

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

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / metabolism
  • Colon / physiology*
  • Colon / physiopathology
  • Cyclooxygenase 1 / deficiency
  • Cyclooxygenase 1 / metabolism
  • Dinoprostone / analysis
  • Dinoprostone / metabolism
  • Female
  • Gastric Mucosa / cytology
  • Gastrointestinal Motility*
  • Gene Expression
  • Macrophages / metabolism*
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Muscle Contraction
  • Myocytes, Smooth Muscle / metabolism*
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism
  • Signal Transduction*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / deficiency
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*


  • CX3C Chemokine Receptor 1
  • Membrane Proteins
  • Receptors, Prostaglandin E
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Cyclooxygenase 1
  • Ptgs1 protein, mouse
  • Dinoprostone