Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions

Liu, Chien-Cheng; Gao, Yong‐Jing; Luo, Hao; Berta, Temugin; Xu, Zhen-Zhong; Ji, Ru-Rong; Tan, Ping-Heng

doi:10.1038/srep34356

Cited by 55 publications

(62 citation statements)

References 58 publications

(87 reference statements)

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“…Our findings clearly demonstrate, however, that one of the earliest responses to viral infection, production of type 1 IFN, causes robust and rapid sensitization of nociceptors via a specific translation regulation signaling cascade. Our findings regarding the action of type I IFNs on nociceptors are opposed to the recent work of Liu et al, (Liu et al, 2016) who found that IFNα causes inhibition of pain signaling at the level of the dorsal horn. These authors proposed that type I IFNs from astrocytes cause presynaptic inhibition of neurotransmitter release from nociceptors therefore reducing pain signaling.…”

Section: Discussioncontrasting

confidence: 99%

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

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Section: Discussioncontrasting

confidence: 99%

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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“…These excitatory interneurons express somatostatin (SOM) [40] . We also recorded CCL2 responses in SOM + neurons in lamina IIo of spinal cord slices from transgenic mice showing SOM expression with tdTomato [25] . These neurons were easily identified by bright fluorescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We also used transgenic C57BL/6 mice (5 weeks) for some electrophysiological experiment. These transgenic mice, obtained from Jackson Laboratory, express tdTomato fluorescence in somatostatin (SOM + ) neurons, after Som -Cre mice were crossed with tdTomato Cre-reporter mice (Rosa26-floxed stop tdTomato mice, Jackson Laboratory), to generate conditional transgenic mice that express tdTomato in SOM + neurons [25] . Adult CD1 mice (male, 8–10 weeks) were used for behavioral and pharmacological studies.…”

Section: Methodsmentioning

confidence: 99%

Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms

et al. 2017

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Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 was shown to enhance NMDA-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms of the CCL2 modulation of central sensitization are still unclear. Spinal injection of the CCR2 antagonist RS504393 attenuated CCL2 and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in vGluT2+ excitatory neurons. CCL2 increased NMDA-induced currents in CCR2+/vGluT2+ neurons in lamina IIo. CCL2 also enhanced evoked synaptic NMDA currents following dorsal root stimulation. Furthermore, CCL2 increased total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest a direct modulation of synaptic plasticity by CCL2 in CCR2-expressing excitatory neurons in the spinal cord lamina IIo underlying the generation of central sensitization in pathological pain.

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“…Generated read counts were analyzed in R version 3.4.4 (R Core Team 2018) via Seurat 2.2.1 35 following its standard pre-processing and clustering workflow (https://satijalab.org/seurat/pbmc3k_tutorial.html). Briefly, from the distribution of reads, the data was filtered to a minimum of 300 cells per gene and 30 genes per cell.…”

Section: Clustering Analysis Of Scrna-seq Datamentioning

confidence: 99%

Single cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

Zheng

Adolacion

et al. 2020

Preprint

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Microglia are heterogeneous and ubiquitous CNS-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single cell RNA-seq (scRNA-seq) analysis to compare the transcriptomes of 32760 microglia in adult mouse (C57/Bl) brains and spinal cords to identify microglial subtypes in these CNS compartments. Cortical microglia from 2-month mice consisted of a predominant population of the homeostatic subtype (HOM-M) and a small population (4%) of the inflammatory subtype (IFLAM-M), while spinal microglia consisted of 55% HOM-M and 45% IFLAM-M subtype. Comparison of cortical and spinal microglia at 2, 4 and 8 months revealed consistently a higher composition of the IFLAM-M subtype in the spinal cord. At 8-month, cortical microglia differentiated a small new subtype with interferon response phenotypes (INF-M), while spinal microglia polarized toward a proinflammatory phenotype, as indicated by the increase of microglia expressing IL-1β. To further characterize the differential plasticity of cortical and spinal microglial heterogeneity, we determined the microglial transcriptomes from HIV-1 gp120 transgenic (Tg) mice, a model of HIV-associated neurological disorders. Compared with wilt-type (Wt) cortical microglia, the gp120tg cortical microglia had three new subtypes, with signatures of interferon I response (INF-M), cell proliferation (PLF-M), and myelination or demyelination (MYE-M) respectively; while INF-M and PLF-M subtypes presented at all ages, the MYE-M only at 4-month.In contrast, only the INF-M subtype was observed in the spinal microglia from 2-and 4-month gp120tg mice. Bioinformatic analysis of regulated molecular pathways of individual microglial subtypes indicated that gp120 more severely impaired the biological function of microglia in cortices than in the spinal cord. The results collectively reveal differential heterogeneity and plasticity of cortical and spinal microglia, and suggest functional differentiation of microglia in different CNS compartments.

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Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions

Cited by 55 publications

References 58 publications

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms

Single cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

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