Abstract
Type I interferons (IFNs) are critical cytokines for antiviral defense and are linked to painful diseases like rheumatoid arthritis, lupus, and neuropathic pain in humans. IFN-α therapy can cause myalgia, headache, and joint and abdominal pain. Studies in rodent models demonstrate that direct action of IFNs on sensory neurons in the dorsal root ganglion (DRG) promotes hyperexcitability, but rodent behavioral data on IFNs are conflicting, with reports of both pro- and antinociceptive actions. We sought to clarify the action of IFN-α and IFN-β on human DRG (hDRG) nociceptors. We found that IFN receptor subunits IFNAR1 and IFNAR2 are expressed by these neurons, and their engagement induces canonical STAT1 signaling and noncanonical MAPK activation as measured by increased phosphorylation of the cap-binding protein elongation initiation factor 4E by MAPK interacting kinases 1/2 (MNK1/2). Using patch-clamp electrophysiology, Ca2+ imaging, and multielectrode arrays, we demonstrated that IFN-α and -β increase the excitability of hDRG neurons with acute and long-term exposure. Type I IFNs prolonged the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. This study supports the conclusion that type I IFNs induce hyperexcitability and transient receptor potential vanilloid 1 sensitization when they interact with IFNAR1/2 in hDRG nociceptors.
Authors
Úrzula Franco-Enzástiga, Keerthana Natarajan, Felipe Espinosa, Rafael Granja-Vazquez, Hemanth Mydugolam, Theodore J. Price
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