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Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.

Publication ,  Journal Article
Chen, Y; Wang, Z-L; Yeo, M; Zhang, Q-J; López-Romero, AE; Ding, H-P; Zhang, X; Zeng, Q; Morales-Lázaro, SL; Moore, C; Jin, Y-A; Yang, H-H ...
Published in: Gastroenterology
July 2021

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.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

July 2021

Volume

161

Issue

1

Start / End Page

301 / 317.e16

Location

United States

Related Subject Headings

  • TRPV Cation Channels
  • Skin
  • Signal Transduction
  • Sensory Receptor Cells
  • Pruritus
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Chicago
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Chen, Y., Wang, Z.-L., Yeo, M., Zhang, Q.-J., López-Romero, A. E., Ding, H.-P., … Liedtke, W. (2021). Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine. Gastroenterology, 161(1), 301-317.e16. https://doi.org/10.1053/j.gastro.2021.03.049
Chen, Yong, Zi-Long Wang, Michele Yeo, Qiao-Juan Zhang, Ana E. López-Romero, Hui-Ping Ding, Xin Zhang, et al. “Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.Gastroenterology 161, no. 1 (July 2021): 301-317.e16. https://doi.org/10.1053/j.gastro.2021.03.049.
Chen Y, Wang Z-L, Yeo M, Zhang Q-J, López-Romero AE, Ding H-P, et al. Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine. Gastroenterology. 2021 Jul;161(1):301-317.e16.
Chen, Yong, et al. “Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.Gastroenterology, vol. 161, no. 1, July 2021, pp. 301-317.e16. Pubmed, doi:10.1053/j.gastro.2021.03.049.
Chen Y, Wang Z-L, Yeo M, Zhang Q-J, López-Romero AE, Ding H-P, Zhang X, Zeng Q, Morales-Lázaro SL, Moore C, Jin Y-A, Yang H-H, Morstein J, Bortsov A, Krawczyk M, Lammert F, Abdelmalek M, Diehl AM, Milkiewicz P, Kremer AE, Zhang JY, Nackley A, Reeves TE, Ko M-C, Ji R-R, Rosenbaum T, Liedtke W. Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine. Gastroenterology. 2021 Jul;161(1):301-317.e16.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

July 2021

Volume

161

Issue

1

Start / End Page

301 / 317.e16

Location

United States

Related Subject Headings

  • TRPV Cation Channels
  • Skin
  • Signal Transduction
  • Sensory Receptor Cells
  • Pruritus
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male