miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

• DOI: 10.1016/j.neuron.2018.06.039
• Publication Date: 2018-07-19T22:55:41Z
• Authors: Qingjian Han; Di Liu; Marino Convertino; Zilong Wang; Changyu Jiang; Yong Ho Kim; Xin Luo; Xin Zhang; Andrea Nackley; Nikolay V. Dokholyan; Ru-Rong Ji
• Keywords: Adult; Aged, 80 and over; Male; Mice, Knockout; Mice, 129 Strain; Adolescent; Extracellular Fluid; CHO Cells; 3. Good health; Mice, Inbred C57BL; Mice; Cricetulus; HEK293 Cells; Mice, Inbred NOD; Cricetinae; Acute Disease; Chronic Disease; Animals; Humans; Female; Cells, Cultured

Increasing evidence suggests that extracellular miRNAs may serve as biomarkers of diseases, but the physiological relevance of extracellular miRNA is unclear. We find that intradermal cheek injection of miR-711 induces TRPA1-depedent itch (scratching) without pain (wiping) in naive mice. Extracellular perfusion of miR-711 induces TRPA1 currents in both Trpa1-expressing heterologous cells and native sensory neurons through the core sequence GGGACCC. Computer simulations reveal that the core sequence binds several residues at the extracellular S5-S6 loop of TRPA1, which are critical for TRPA1 activation by miR-711 but not allyl isothiocyanate. Intradermal inoculation of human Myla cells induces lymphoma and chronic itch in immune-deficient mice, associated with increased serum levels of miR-711, secreted from cancer cells. Lymphoma-induced chronic itch is suppressed by miR-711 inhibitor and a blocking peptide that disrupts the miR-711/TRPA1 interaction. Our findings demonstrated an unconventional physiological role of extracellular naked miRNAs as itch mediators and ion channel modulators.