Gastroenterology

Gastroenterology

Volume 161, Issue 1, July 2021, Pages 301-317.e16
Gastroenterology

Original Research
Full Report: Basic and Translational—Liver
Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine

https://doi.org/10.1053/j.gastro.2021.03.049Get rights and content
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Background & Aims

Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.

Methods

Pruritogenicity of lysophosphatidylcholine (LPC), LPA’s precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC’s pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a.

Results

LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates.

Conclusions

We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.

Keywords

Lysophosphatidylcholine
Cholestatic Itch
Keratinocyte TRPV4
miR-146a
TRPV1 Pruriceptor

Abbreviations used in this paper

ANIT
α-naphthyl-isothiocyanate
DRG
dorsal root ganglion
ERK
extracellular signal-regulated kinase
ID
intradermal
IT
intrathecal
KO
knockout
LPA
lysophosphatidic acid
LPC
lysophosphatidylcholine
MEK
mitogen-activated protein kinase
miR
microRNA
PBC
primary biliary cholangitis
TRP
transient receptor potential
HEK
human embryonic kidney
h
human
r
rat
p-
phosphorylated
tam
tamoxifen
TLR
Toll-like receptors
WT
wild-type

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Conflicts of interest The authors disclose no conflicts.

Funding This work was supported by National Institutes of Health, National Institute of Dental & Craniofacial (NIDCR) research grant DE018549, by a Duke University Chancellor's Discovery Award and by the Michael Ross Haffner Foundation (Charlotte, NC) to W.L., NIDCR grants K12DE022793 and R01DE027454 to Y.C., by a Duke Chancellor's Discovery Award to J.Y.Z., and Dirección General de Asuntos del Personal Académico (DGAPA)-Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) grant IN200720, Consejo Nacional de Ciencia y Tecnología (CONACyT) grant A1-S-8760, and Secretaría de Educación, Ciencia, Tecnología e Innovación del Gobierno de la Ciudad de México grant SECTEI/208/2019 to T.R.

Author names in bold designate shared co-first authorship.

Authors share co-first authorship.