Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1.
Intracellular microRNAs (miRNAs) are key regulators of gene expression. The role of extracellular miRNAs in neuronal activation and sensory behaviors are unknown. Here we report an unconventional role of extracellular miRNAs for rapid excitation of nociceptor neurons via toll-like receptor-7 (TLR7) and its coupling to TRPA1 ion channel. miRNA-let-7b induces rapid inward currents and action potentials in dorsal root ganglion (DRG) neurons. These responses require the GUUGUGU motif, only occur in neurons coexpressing TLR7 and TRPA1, and are abolished in mice lacking Tlr7 or Trpa1. Furthermore, let-7b induces TLR7/TRPA1-dependent single-channel activities in DRG neurons and HEK293 cells overexpressing TLR7/TRPA1. Intraplantar injection of let-7b elicits rapid spontaneous pain via TLR7 and TRPA1. Finally, let-7b can be released from DRG neurons by neuronal activation, and let-7b inhibitor reduces formalin-induced TRPA1 currents and spontaneous pain. Thus, secreted extracellular miRNAs may serve as novel pain mediators via activating TLR7/TRPA1 in nociceptor neurons.
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Chul-Kyu
CK
Park
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Zhen-Zhong
ZZ
Xu
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Temugin
T
Berta
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Qingjian
Q
Han
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Gang
G
Chen
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Xing-Jun
XJ
Liu
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: ru-rong.ji@duke.edu.
Ru-Rong
RR
Ji
D000818:Animals; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000009:adverse effects* / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced* / Q000473:pathology; D059408:Pain Management; D018408:Patch-Clamp Techniques; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000172:deficiency; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D008562:Membrane Glycoproteins; D035683:MicroRNAs; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D005557:Formaldehyde