Epithelia-sensory neuron crosstalk underlies cholestatic itch induced by lysophosphatidylcholine.

BACKGROUND & AIMS Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of anti-pruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. METHODS Pruritogenicity of LPC, LPA’s precursor, was examined in naive mice, cholestatic mice, and nonhuman primates. LPC’s pruritogenicity involving keratinocyte-TRPV4 was studied using genetic and pharmacological 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 primary biliary cholangitis (PBC) patients 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. 3D-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. Both LPC and miR-146a levels were elevated in sera of PBC patients 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 crosstalk, whereby it directly activates skin keratinocyte-TRPV4, which rapidly release 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.