Immunity
Volume 49, Issue 1, 17 July 2018, Pages 107-119.e4
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Article
TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells

https://doi.org/10.1016/j.immuni.2018.04.021Get rights and content
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Highlights

  • Macrophage-specific Trpv4-deficient mice display reduced gastrointestinal motility

  • Direct interactions between MMs and smooth muscle cells produce colon contraction

  • Enteric nervous system is not involved in macrophage-mediated colon contraction

  • TRPV4 inhibition reverses GI hypermotility associated with chemotherapy treatment

Summary

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

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

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Present address: A.A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, 4 Bogomoletz Street, 01024 Kyiv, Ukraine

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