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Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.

Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA - Mol Pain (2009)

Bottom Line: Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior.In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100.These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pharmacology, Northwestern University, Chicago, IL, USA. bhangoos@nidcr.nih.gov

ABSTRACT
Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

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Chemokine expression after gp120/hCD4 alone and following the combination of gp120/hCD4 and ddC treatment. A) MCP1 expression, the ligand for the CCR2 receptor was absent from sham treated animals. B) After gp120/hCD4 treatment, MCP1 expression was upregulated in mostly neurons of the DRG. C) After the combined treatments of gp120/hCD4 and ddC, MCP1 expression was upregulated in a similar manner to that seen in the gp120/hCD4 only treatment. D) SDF1, the ligand for CXCR4, had a basal level of mRNA expression, with the occasional neuron staining positive for the chemokine E) After gp120/hCD4 treatment, the level of SDF1 mRNA expression did not change appreciably, when compared to sham treated animals. F) Following gp120/hCD4 and ddC treatments, SDF1 mRNA expression was upregulated in neurons of all sizes. Arrows: positive cells; arrowheads: negative cells. Scale bar: 100 um.
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Figure 6: Chemokine expression after gp120/hCD4 alone and following the combination of gp120/hCD4 and ddC treatment. A) MCP1 expression, the ligand for the CCR2 receptor was absent from sham treated animals. B) After gp120/hCD4 treatment, MCP1 expression was upregulated in mostly neurons of the DRG. C) After the combined treatments of gp120/hCD4 and ddC, MCP1 expression was upregulated in a similar manner to that seen in the gp120/hCD4 only treatment. D) SDF1, the ligand for CXCR4, had a basal level of mRNA expression, with the occasional neuron staining positive for the chemokine E) After gp120/hCD4 treatment, the level of SDF1 mRNA expression did not change appreciably, when compared to sham treated animals. F) Following gp120/hCD4 and ddC treatments, SDF1 mRNA expression was upregulated in neurons of all sizes. Arrows: positive cells; arrowheads: negative cells. Scale bar: 100 um.

Mentions: The number of cells exhibiting MCP1 (immunoreactivity) or SDF1 (mRNA transcripts), the respective ligands for the CCR2 and CXCR4 receptors, were also analyzed using the both injury paradigms. Under sham conditions, there were virtually no MCP1 immunopositive neurons in the lumbar DRG (Fig. 6A). In sharp contrast, numerous MCP1 immunopositive neurons were present in lumbar ganglia of the gp120/hCD4 treated rats by POD 14 (Fig. 6B). There was also a complete lack of MCP1 immunopositive non-neuronal cells in injured DRG at any time point.


Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.

Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA - Mol Pain (2009)

Chemokine expression after gp120/hCD4 alone and following the combination of gp120/hCD4 and ddC treatment. A) MCP1 expression, the ligand for the CCR2 receptor was absent from sham treated animals. B) After gp120/hCD4 treatment, MCP1 expression was upregulated in mostly neurons of the DRG. C) After the combined treatments of gp120/hCD4 and ddC, MCP1 expression was upregulated in a similar manner to that seen in the gp120/hCD4 only treatment. D) SDF1, the ligand for CXCR4, had a basal level of mRNA expression, with the occasional neuron staining positive for the chemokine E) After gp120/hCD4 treatment, the level of SDF1 mRNA expression did not change appreciably, when compared to sham treated animals. F) Following gp120/hCD4 and ddC treatments, SDF1 mRNA expression was upregulated in neurons of all sizes. Arrows: positive cells; arrowheads: negative cells. Scale bar: 100 um.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2734548&req=5

Figure 6: Chemokine expression after gp120/hCD4 alone and following the combination of gp120/hCD4 and ddC treatment. A) MCP1 expression, the ligand for the CCR2 receptor was absent from sham treated animals. B) After gp120/hCD4 treatment, MCP1 expression was upregulated in mostly neurons of the DRG. C) After the combined treatments of gp120/hCD4 and ddC, MCP1 expression was upregulated in a similar manner to that seen in the gp120/hCD4 only treatment. D) SDF1, the ligand for CXCR4, had a basal level of mRNA expression, with the occasional neuron staining positive for the chemokine E) After gp120/hCD4 treatment, the level of SDF1 mRNA expression did not change appreciably, when compared to sham treated animals. F) Following gp120/hCD4 and ddC treatments, SDF1 mRNA expression was upregulated in neurons of all sizes. Arrows: positive cells; arrowheads: negative cells. Scale bar: 100 um.
Mentions: The number of cells exhibiting MCP1 (immunoreactivity) or SDF1 (mRNA transcripts), the respective ligands for the CCR2 and CXCR4 receptors, were also analyzed using the both injury paradigms. Under sham conditions, there were virtually no MCP1 immunopositive neurons in the lumbar DRG (Fig. 6A). In sharp contrast, numerous MCP1 immunopositive neurons were present in lumbar ganglia of the gp120/hCD4 treated rats by POD 14 (Fig. 6B). There was also a complete lack of MCP1 immunopositive non-neuronal cells in injured DRG at any time point.

Bottom Line: Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior.In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100.These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pharmacology, Northwestern University, Chicago, IL, USA. bhangoos@nidcr.nih.gov

ABSTRACT
Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

Show MeSH
Related in: MedlinePlus