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J Allergy Clin Immunol. 2018 Feb;141(2):608-619.e7. doi: 10.1016/j.jaci.2017.05.051. Epub 2017 Aug 11.

Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.

Author information

1
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, Mo.
2
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, Mo; School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, China.
3
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Tex.
4
Department of Anatomy, Chongqing Medical University, Chongqing, China.
5
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China.
6
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Tex.
7
College of Pharmacy, South-Central University for Nationalities, Wuhan, China.
8
Department of Medicine, Baylor College of Medicine, Houston, Tex.
9
Brown Foundation Institute of Molecular Medicine and Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, Tex.
10
Department of Integrative Biology and Pharmacology, the University of Texas Medical School at Houston, Houston, Tex.
11
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Mo.
12
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, Mo; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Mo.
13
Center for Brain and Behavior Research, Biology Department, University of South Dakota, Vermillion, SD.
14
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, Mo. Electronic address: qinliu@wustl.edu.
15
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, Mo. Electronic address: huh@anest.wustl.edu.

Abstract

BACKGROUND:

Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin-associated cells remains poorly understood.

OBJECTIVE:

We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4)-mediated allergic and nonallergic chronic itch.

METHODS:

Expression of TRPV4 in chronic itch and healthy control skin preparations was examined by using real-time RT-PCR. Trpv4eGFP mice were used to study the expression and function of TRPV4 in the skin by means of immunofluorescence staining, flow cytometry, calcium imaging, and patch-clamp recordings. Genetic and pharmacologic approaches were used to examine the role and underlying mechanisms of TRPV4 in mouse models of dry skin-associated chronic itch and spontaneous scratching associated with squaric acid dibutylester-induced allergic contact dermatitis.

RESULTS:

TRPV4 is selectively expressed by dermal macrophages and epidermal keratinocytes in mice. Lineage-specific deletion of TRPV4 in macrophages and keratinocytes reduces allergic and nonallergic chronic itch in mice, respectively. Importantly, TRPV4 expression is significantly increased in skin biopsy specimens from patients with chronic idiopathic pruritus in comparison with skin from healthy control subjects. Moreover, TRPV4-dependent chronic itch requires 5-hydroxytryptamine (5-HT) signaling secondary to activation of distinct 5-HT receptors in mice with allergic and those with nonallergic chronic itch conditions.

CONCLUSION:

Our study reveals previously unrecognized mechanisms by which TRPV4-expressing epithelial and immune cells in the skin critically and dynamically mediate chronic itch and unravels novel targets for therapeutics in the setting of chronic itch.

KEYWORDS:

Transient receptor potential vanilloid 4; chronic itch; keratinocyte; macrophage

PMID:
28807414
PMCID:
PMC5799031
DOI:
10.1016/j.jaci.2017.05.051
[Indexed for MEDLINE]
Free PMC Article

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