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

View Article: PubMed Central - PubMed

ABSTRACT

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

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IFN-α expression in cultured astrocytes.(A–D) Triple staining of IFN-α (A), GFAP (B), and nucleus marker DAPI (C) in astrocytes. D is the merge of A-C. Scales, 30 μm. (E,F) High magnification image showing triple staining of IFN-α (E), GFAP, and DAPI (F). E is a single staining panel and F is the merge of all 3 images. Arrows indicate IFN-α-labeled vesicles in remote astrocyte processes. Scales, 10 μm.
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f6: IFN-α expression in cultured astrocytes.(A–D) Triple staining of IFN-α (A), GFAP (B), and nucleus marker DAPI (C) in astrocytes. D is the merge of A-C. Scales, 30 μm. (E,F) High magnification image showing triple staining of IFN-α (E), GFAP, and DAPI (F). E is a single staining panel and F is the merge of all 3 images. Arrows indicate IFN-α-labeled vesicles in remote astrocyte processes. Scales, 10 μm.

Mentions: Next, we examined IFN-α expression in primary cultures of astrocytes. Immunocytochemistry showed marked IFN-α expression in astrocytes (Fig. 6A). We used the nuclei marker DAPI to stain cells in the cultures, and our data indicated that almost all cells (DAPI+) in cultures expressed GFAP, suggesting that our astrocyte cultures were not contaminated by other cell types (Fig. 6B–D). We found that all IFN-α-positive cells expressed GFAP. Interestingly, IFN-α was observed in vesicles of cytoplasm and remote processes of astrocytes (Fig. 6E,F).


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
IFN-α expression in cultured astrocytes.(A–D) Triple staining of IFN-α (A), GFAP (B), and nucleus marker DAPI (C) in astrocytes. D is the merge of A-C. Scales, 30 μm. (E,F) High magnification image showing triple staining of IFN-α (E), GFAP, and DAPI (F). E is a single staining panel and F is the merge of all 3 images. Arrows indicate IFN-α-labeled vesicles in remote astrocyte processes. Scales, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037469&req=5

f6: IFN-α expression in cultured astrocytes.(A–D) Triple staining of IFN-α (A), GFAP (B), and nucleus marker DAPI (C) in astrocytes. D is the merge of A-C. Scales, 30 μm. (E,F) High magnification image showing triple staining of IFN-α (E), GFAP, and DAPI (F). E is a single staining panel and F is the merge of all 3 images. Arrows indicate IFN-α-labeled vesicles in remote astrocyte processes. Scales, 10 μm.
Mentions: Next, we examined IFN-α expression in primary cultures of astrocytes. Immunocytochemistry showed marked IFN-α expression in astrocytes (Fig. 6A). We used the nuclei marker DAPI to stain cells in the cultures, and our data indicated that almost all cells (DAPI+) in cultures expressed GFAP, suggesting that our astrocyte cultures were not contaminated by other cell types (Fig. 6B–D). We found that all IFN-α-positive cells expressed GFAP. Interestingly, IFN-α was observed in vesicles of cytoplasm and remote processes of astrocytes (Fig. 6E,F).

View Article: PubMed Central - PubMed

ABSTRACT

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

No MeSH data available.


Related in: MedlinePlus