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

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

Author information

1
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China.
3
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Anatomy, Chongqing Medical University, Chongqing 400016, China.
5
College of Pharmacy, South-Central University for Nationalities, Wuhan, Hubei 430073, China.
6
Department of Biophysics, Institute of Biology, Taras Shevchenko National University of Kyiv, Kyiv 03022, Ukraine.
7
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
8
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
9
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: briankim@wustl.edu.
10
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: hongzhen.hu@wustl.edu.

Abstract

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

PMID:
29958798
PMCID:
PMC6051912
[Available on 2019-07-17]
DOI:
10.1016/j.immuni.2018.04.021

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