Type I Interferon-Mediated Signaling Produces Nociceptive Pain

Post by Amanda McFarlan 

What's the science?

Viral infections can cause both acute and chronic neuropathic pain. However, the mechanisms by which these neuropathies occur are still poorly understood. Type I interferons (IFNs) are cytokines that are rapidly released by a variety of cells in response to viral infection and therefore, these IFNs may be an ideal candidate for mediating viral-induced neuropathic pain by directly binding nociceptors in the body’s peripheral nervous system. This week in the Journal of Neuroscience, Barragán-Iglesias and colleagues investigated the role of type I IFNs in mediating nociceptive pain responses. 

How did they do it?

The authors used the von Frey filament test (to test mechanical sensitivity) and the Hargreaves test (to test thermal pain sensitivity) to evaluate the nociceptive responses in mice following intraplantar (in the foot) injections of IFN-α, IFN-β or saline. Because they found that IFN administration caused a pain response in mice, the authors used RNAscope in situ hybridization (detects RNA in intact cells) to determine whether IFN receptors could be found in the dorsal root ganglion (a cluster of neurons in the spinal cord that relays sensory information to the brain). To investigate the effect of IFN on downstream signaling in the cell, the authors applied IFN-α and IFN-β to cultured dorsal root ganglion neurons and performed western blots to identify which downstream signaling molecules were present. Since the MNK-eIF4E pathway (involved in nociception) was found to be activated by IFN, the authors performed intraplantar injections of IFN-α and IFN-β in transgenic mice with disrupted MNK-eIF4E pathways to investigate the role of this pathway in IFN-mediated pain responses. Next, the authors used patch-clamp electrophysiology in cultured dorsal root ganglion neurons treated with IFN-α to examine the effects of IFN on neuronal excitability. Finally, the authors investigated the role of endogenous IFN in the pain response. To do this, they simulated a viral infection by injecting poly I:C (an immunostimulant) in transgenic mice with disrupted MNK-eIF4E pathways and wild-type mice and then measured mechanical and thermal pain sensitivity. 

What did they find?

The authors found that administration of IFN-α and IFN-β, but not saline, in mice caused increased hypersensitivity to mechanical stimulation with no change in sensitivity to thermal stimulation. They confirmed that the majority of dorsal root ganglion cells expressed the subunits for IFN receptors, suggesting that IFN-mediated nociceptive responses are communicated to the brain via these receptors. Then, the authors determined that the application of IFN-α and IFN-β quickly activated downstream signaling molecules in the MNK-eIF4E pathway. They found that compared to controls, transgenic mice with disruptions in the MNK-eIF4E pathway had reduced hypersensitivity to mechanical stimulation following IFN administration, suggesting this pathway is critical for IFN-mediated nociceptive pain responses. Next, the authors determined that dorsal root ganglion neurons treated with IFN had increased neuronal excitability compared to controls. Notably, treatment with IFN reduced the latency of action potential initiation, suggesting that IFN-mediated responses in dorsal root ganglion neurons cause rapid neuronal hyperexcitability that coincides with activation of the MNK-eIF4E pathway.

Finally, the authors showed that administration of poly I:C increased mechanical and thermal hypersensitivity in wild-type mice, but not in transgenic mice with disrupted MNK-eIF4E pathways. They found that direct application of poly I:C to dorsal root ganglion neurons did not cause an increase in the signaling molecules in the MNK-eIF4E pathway, which suggests that the in vivo nociceptive response to poly I:C is likely mediated by the endogenous release of IFN that acts on dorsal root ganglion neurons. 

What’s the impact?

This is the first study to provide evidence for a mechanism by which a viral infection, which causes the release of IFN, can rapidly induce nociceptive responses. The authors showed that type 1 IFNs act via the MNK-eIF4E signaling pathway to produce increased mechanical hypersensitivity. Together, these findings highlight the relevance of the IFN to MNK-eIF4E pathway as a potential target for the development of treatments to alleviate viral-induced acute and chronic neuropathic pain. 

Barragán-Iglesias et al. Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain. The Journal of Neuroscience (2020). Access the original scientific publication here.