To assess the potential role of IL-6 in sciatic nerve injury-induced activation of a pro-regenerative state in remote dorsal root ganglia (DRG) neurons, we compared protein levels of SCG-10 and activated STAT3, as well as axon regeneration in IL-6 knockout (IL-6ko) mice and their wild-type (WT) counterparts. Unilateral sciatic nerve compression and transection upregulated SCG-10 protein levels and activated STAT3 in DRG neurons not only in lumbar but also in cervical segments of WT mice. A pro-regenerative state induced by prior sciatic nerve lesion in cervical DRG neurons of WT mice was also shown by testing for axon regeneration in crushed ulnar nerve. DRG neurons from IL-6ko mice also displayed bilaterally increased levels of SCG-10 and STAT3 in both lumbar and cervical segments after sciatic nerve lesions. However, levels of SCG-10 protein in lumbar and cervical DRG of IL-6ko mice were significantly lower than those of their WT counterparts. Sciatic nerve injury induced a lower level of SCG-10 in cervical DRG of IL-6ko than WT mice, and this correlates with significantly shorter regeneration of axons distal to the crushed ulnar nerve. These results suggest that IL-6 contributes, at the very least, to initiation of the neuronal regeneration program in remote DRG neurons after unilateral sciatic nerve injury.

• Keywords
• Primary sensory neuron, SCG10, STAT3, Sciatic nerve lesion, Ulnar nerve crush,
• MeSH
• Immunohistochemistry MeSH
• Interleukin-6 analysis   deficiency   metabolism   MeSH
• Intracellular Signaling Peptides and Proteins analysis   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurons chemistry   cytology   metabolism   pathology   MeSH
• Peripheral Nerve Injuries metabolism   pathology   surgery   MeSH
• Calcium-Binding Proteins MeSH
• Nerve Regeneration * MeSH
• Ganglia, Spinal cytology   metabolism   pathology   surgery   MeSH
• Stathmin MeSH
• STAT3 Transcription Factor analysis   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Interleukin-6 MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Calcium-Binding Proteins MeSH
• Stat3 protein, mouse MeSH Browser
• Stathmin MeSH
• Stmn2 protein, mouse MeSH Browser
• STAT3 Transcription Factor MeSH

The primary sensory neurons of dorsal root ganglia (DRG) are a very useful model to study the neuronal regenerative program that is a prerequisite for successful axon regeneration after peripheral nerve injury. Seven days after a unilateral sciatic nerve injury by compression or transection, we detected a bilateral increase in growth-associated protein-43 (GAP-43) and superior cervical ganglion-10 (SCG-10) mRNA and protein levels not only in DRG neurons of lumbar spinal cord segments (L4-L5) associated with injured nerve, but also in remote cervical segments (C6-C8). The increase in regeneration-associated proteins in the cervical DRG neurons was associated with the greater length of regenerated axons 1 day after ulnar nerve crush following prior sciatic nerve injury as compared to controls with only ulnar nerve crush. The increased axonal regeneration capacity of cervical DRG neurons after a prior conditioning sciatic nerve lesion was confirmed by neurite outgrowth assay of in vitro cultivated DRG neurons. Intrathecal injection of IL-6 or a JAK2 inhibitor (AG490) revealed a role for the IL-6 signaling pathway in activating the pro-regenerative state in remote DRG neurons. Our results suggest that the pro-regenerative state induced in the DRG neurons non-associated with the injured nerve reflects a systemic reaction of these neurons to unilateral sciatic nerve injury.

• Keywords
• GAP-43, IL-6, SCG-10, neurite outgrowth assay, primary sensory neurons, pro-regenerative state, ulnar nerve crush, unilateral nerve injury,
• Publication type
• Journal Article MeSH

Unilateral sciatic nerve compression (SNC) or complete sciatic nerve transection (CSNT), both varying degrees of nerve injury, induced activation of STAT3 bilaterally in the dorsal root ganglia (DRG) neurons of lumbar (L4-L5) as well as cervical (C6-C8) spinal cord segments. STAT3 activation was by phosphorylation at the tyrosine-705 (Y705) and serine-727 (S727) positions and was followed by their nuclear translocation. This is the first evidence of STAT3(S727) activation together with the well-known activation of STAT3(Y705) in primary sensory neurons upon peripheral nerve injury. Bilateral activation of STAT3 in DRG neurons of spinal segments anatomically both associated as well as non-associated with the injured nerve indicates diffusion of STAT3 activation inducers along the spinal cord. Increased levels of IL-6 protein in the CSF following nerve injury as well as activation and nuclear translocation of STAT3 in DRG after intrathecal injection of IL-6 shows that this cytokine, released into the subarachnoid space can penetrate the DRG to activate STAT3. Previous results on increased bilateral IL-6 synthesis and the present manifestation of STAT3 activation in remote DRG following unilateral sciatic nerve injury may reflect a systemic reaction of the DRG neurons to nerve injury.

• Keywords
• Dorsal root ganglia, Neuroinflammation, Peripheral nerve injury, Systemic reaction,
• MeSH
• Active Transport, Cell Nucleus MeSH
• Cell Nucleus metabolism   MeSH
• Phosphorylation MeSH
• Phosphoserine metabolism   MeSH
• Phosphotyrosine metabolism   MeSH
• Rats MeSH
• Sciatic Neuropathy metabolism   pathology   MeSH
• Sensory Receptor Cells metabolism   pathology   MeSH
• Rats, Wistar MeSH
• Ganglia, Spinal metabolism   pathology   MeSH
• STAT3 Transcription Factor chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phosphoserine MeSH
• Phosphotyrosine MeSH
• Stat3 protein, rat MeSH Browser
• STAT3 Transcription Factor MeSH

BACKGROUND: Interaction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases. METHODS: Immunofluorescence staining, western blot analysis, and RT-PCR were used to investigate the modulatory effects of CD200 fusion protein (CD200Fc) on activation of microglia and astrocytes as well as synthesis of pro- (TNF, IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines in the L4-L5 spinal cord segments in relation to behavioral signs of neuropathic pain after unilateral sterile chronic constriction injury (sCCI) of the sciatic nerve. Withdrawal thresholds for mechanical hypersensitivity and latencies for thermal hypersensitivity were measured in hind paws 1 day before operation; 1, 3, and 7 days after sCCI operation; and then 5 and 24 h after intrathecal application of artificial cerebrospinal fluid or CD200Fc. RESULTS: Seven days from sCCI operation and 5 h from intrathecal application, CD200Fc reduced mechanical and thermal hypersensitivity when compared with control animals. Simultaneously, CD200Fc attenuated activation of glial cells and decreased proinflammatory and increased anti-inflammatory cytokine messenger RNA (mRNA) levels. Administration of CD200Fc also diminished elevation of CD200 and CD200R proteins as a concomitant reaction of the modulatory system to increased neuroinflammatory reactions after nerve injury. The anti-inflammatory effect of CD200Fc dropped at 24 h after intrathecal application. CONCLUSIONS: Intrathecal administration of the CD200R1 agonist CD200Fc induces very rapid suppression of neuroinflammatory reactions associated with glial activation and neuropathic pain development. This may constitute a promising and novel therapeutic approach for the treatment of neuropathic pain.

• MeSH
• Antigens, Surface pharmacology   therapeutic use   MeSH
• Time Factors MeSH
• Antigens, CD metabolism   MeSH
• Cytokines genetics   metabolism   MeSH
• Physical Stimulation adverse effects   MeSH
• Glial Fibrillary Acidic Protein metabolism   MeSH
• Hyperalgesia drug therapy   etiology   MeSH
• Sciatica complications   drug therapy   MeSH
• Rats MeSH
• Spinal Cord drug effects   metabolism   MeSH
• Disease Models, Animal MeSH
• Neuroglia drug effects   metabolism   MeSH
• Orexin Receptors MeSH
• Rats, Wistar MeSH
• Pain Threshold drug effects   MeSH
• Receptors, Cell Surface antagonists & inhibitors   therapeutic use   MeSH
• Gene Expression Regulation drug effects   MeSH
• Injections, Spinal MeSH
• Inflammation drug therapy   etiology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• antigens, CD200 MeSH Browser
• Antigens, Surface MeSH
• Antigens, CD MeSH
• CD200R1 protein, human MeSH Browser
• Cytokines MeSH
• Glial Fibrillary Acidic Protein MeSH
• Orexin Receptors MeSH
• Receptors, Cell Surface MeSH