Limits...
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.

No MeSH data available.


Related in: MedlinePlus

IFN-α expression in the spinal cord dorsal horn.(A) Immunohistochemistry showing IFN-α-expression in the spinal cord dorsal horn. Scale, 100 μm. (B–D) Double staining of IFN-α (B) and GFAP (C) in the superficial spinal cord dorsal horn. D is the merge of B and C. Scales, 50 μm. (E) High magnification image showing double staining of IFN-α and GFAP in the superficial spinal cord dorsal horn. Arrows indicate double-labeled astrocytes. Arrows indicate double-labeled cells. Scales, 25 μm. (F,G) Double staining of IFN-α with the neuronal marker NeuN (F) and microglial marker OX-42 (G) in the superficial spinal cord dorsal horn. Scales, 10 μm. (H) Absence of IFN-α immunostaining in the dorsal horn after absorption with a blocking peptide. Scale, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5037469&req=5

f5: IFN-α expression in the spinal cord dorsal horn.(A) Immunohistochemistry showing IFN-α-expression in the spinal cord dorsal horn. Scale, 100 μm. (B–D) Double staining of IFN-α (B) and GFAP (C) in the superficial spinal cord dorsal horn. D is the merge of B and C. Scales, 50 μm. (E) High magnification image showing double staining of IFN-α and GFAP in the superficial spinal cord dorsal horn. Arrows indicate double-labeled astrocytes. Arrows indicate double-labeled cells. Scales, 25 μm. (F,G) Double staining of IFN-α with the neuronal marker NeuN (F) and microglial marker OX-42 (G) in the superficial spinal cord dorsal horn. Scales, 10 μm. (H) Absence of IFN-α immunostaining in the dorsal horn after absorption with a blocking peptide. Scale, 100 μm.

Mentions: Immunofluorescence showed IFN-α immunoreactivity in the spinal cord dorsal horn (Fig. 5A). Double immunofluorescence revealed that IFN-α was predominantly expressed in spinal cord astrocytes expressing GFAP (Fig. 5B–E). IFN-α was not found in neurons (NeuN+) in the dorsal horn (Fig. 5F). Few microglial cells (OX-42+) also expressed IFN-α (Fig. 5G). IFN-α immunostaining was lost after absorption of the primary antibody with a specific blocking peptide (Fig. 5H) or after omission of primary antibody (data not shown), supporting the specificity of the staining.


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
IFN-α expression in the spinal cord dorsal horn.(A) Immunohistochemistry showing IFN-α-expression in the spinal cord dorsal horn. Scale, 100 μm. (B–D) Double staining of IFN-α (B) and GFAP (C) in the superficial spinal cord dorsal horn. D is the merge of B and C. Scales, 50 μm. (E) High magnification image showing double staining of IFN-α and GFAP in the superficial spinal cord dorsal horn. Arrows indicate double-labeled astrocytes. Arrows indicate double-labeled cells. Scales, 25 μm. (F,G) Double staining of IFN-α with the neuronal marker NeuN (F) and microglial marker OX-42 (G) in the superficial spinal cord dorsal horn. Scales, 10 μm. (H) Absence of IFN-α immunostaining in the dorsal horn after absorption with a blocking peptide. Scale, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037469&req=5

f5: IFN-α expression in the spinal cord dorsal horn.(A) Immunohistochemistry showing IFN-α-expression in the spinal cord dorsal horn. Scale, 100 μm. (B–D) Double staining of IFN-α (B) and GFAP (C) in the superficial spinal cord dorsal horn. D is the merge of B and C. Scales, 50 μm. (E) High magnification image showing double staining of IFN-α and GFAP in the superficial spinal cord dorsal horn. Arrows indicate double-labeled astrocytes. Arrows indicate double-labeled cells. Scales, 25 μm. (F,G) Double staining of IFN-α with the neuronal marker NeuN (F) and microglial marker OX-42 (G) in the superficial spinal cord dorsal horn. Scales, 10 μm. (H) Absence of IFN-α immunostaining in the dorsal horn after absorption with a blocking peptide. Scale, 100 μm.
Mentions: Immunofluorescence showed IFN-α immunoreactivity in the spinal cord dorsal horn (Fig. 5A). Double immunofluorescence revealed that IFN-α was predominantly expressed in spinal cord astrocytes expressing GFAP (Fig. 5B–E). IFN-α was not found in neurons (NeuN+) in the dorsal horn (Fig. 5F). Few microglial cells (OX-42+) also expressed IFN-α (Fig. 5G). IFN-α immunostaining was lost after absorption of the primary antibody with a specific blocking peptide (Fig. 5H) or after omission of primary antibody (data not shown), supporting the specificity of the staining.

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