Nitrosative damage during retrovirus infection-induced neuropathic pain
Abstract Background Peripheral neuropathy is currently the most common neurological complication in HIV-infected individuals, occurring in 35–50% of patients undergoing combination anti-retroviral therapy. Data have shown that distal symmetric polyneuropathy develops in mice by 6 weeks following inf...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-03-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1107-7 |
| _version_ | 1818943146858381312 |
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| author | Priyanka Chauhan Wen S. Sheng Shuxian Hu Sujata Prasad James R. Lokensgard |
| author_facet | Priyanka Chauhan Wen S. Sheng Shuxian Hu Sujata Prasad James R. Lokensgard |
| author_sort | Priyanka Chauhan |
| collection | DOAJ |
| description | Abstract Background Peripheral neuropathy is currently the most common neurological complication in HIV-infected individuals, occurring in 35–50% of patients undergoing combination anti-retroviral therapy. Data have shown that distal symmetric polyneuropathy develops in mice by 6 weeks following infection with the LP-BM5 retrovirus mixture. Previous work from our laboratory has demonstrated that glial cells modulate antiviral T-cell effector responses through the programmed death (PD)-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Methods Using the MouseMet electronic von Frey system, we assessed hind-paw mechanical hypersensitivity in LP-BM5-infected wild-type (WT) and PD-1 KO animals. Using multi-color flow cytometry, we quantitatively assessed cellular infiltration and microglial activation. Using real-time RT-PCR, we assessed viral load, expression of IFN-γ, iNOS, and MHC class II. Using western blotting, we measured protein nitrosylation within the lumbar spinal cord (LSC) and dorsal root ganglion (DRG). Histochemical staining was performed to analyze the presence of CD3, ionized calcium binding adaptor molecule (Iba)-1, MHCII, nitrotyrosine, isolectin B4 (IB4) binding, and neurofilament 200 (NF200). Statistical analyses were carried out using graphpad prism. Results Hind-paw mechanical hypersensitivity observed in LP-BM5-infected animals was associated with significantly increased lymphocyte infiltration into the spinal cord and DRG. We also observed elevated expression of IFN-γ (in LSC and DRG) and MHC II (on resident microglia in LSC). We detected elevated levels of 3-nitrotyrosine within the LSC and DRG of LP-BM5-infected animals, an indicator of nitric oxide (NO)-induced protein damage. Moreover, we observed 3-nitrotyrosine in both small (IB4+) and large (NF200+) DRG sensory neurons. Additionally, infected PD-1 KO animals displayed significantly greater mechanical hypersensitivity than WT or uninfected mice at 4 weeks post-infection (p.i.). Accelerated onset of hind-paw hypersensitivity in PD-1 KO animals was associated with significantly increased infiltration of CD4+ and CD8+ T lymphocytes, macrophages, and microglial activation at early time points. Importantly, we also observed elevated levels of 3-nitrotyrosine and iNOS in infected PD-1 KO animals when compared with WT animals. Conclusions Results reported here connect peripheral immune cell infiltration and reactive gliosis with nitrosative damage. These data may help elucidate how retroviral infection-induced neuroinflammatory networks contribute to nerve damage and neuropathic pain. |
| first_indexed | 2024-12-20T07:22:42Z |
| format | Article |
| id | doaj.art-b47ed7d07c6e49d0bd1617e471317715 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T07:22:42Z |
| publishDate | 2018-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b47ed7d07c6e49d0bd1617e4713177152022-12-21T19:48:39ZengBMCJournal of Neuroinflammation1742-20942018-03-0115111610.1186/s12974-018-1107-7Nitrosative damage during retrovirus infection-induced neuropathic painPriyanka Chauhan0Wen S. Sheng1Shuxian Hu2Sujata Prasad3James R. Lokensgard4Department of Medicine, Neurovirology Laboratory, University of Minnesota Medical SchoolDepartment of Medicine, Neurovirology Laboratory, University of Minnesota Medical SchoolDepartment of Medicine, Neurovirology Laboratory, University of Minnesota Medical SchoolDepartment of Medicine, Neurovirology Laboratory, University of Minnesota Medical SchoolDepartment of Medicine, Neurovirology Laboratory, University of Minnesota Medical SchoolAbstract Background Peripheral neuropathy is currently the most common neurological complication in HIV-infected individuals, occurring in 35–50% of patients undergoing combination anti-retroviral therapy. Data have shown that distal symmetric polyneuropathy develops in mice by 6 weeks following infection with the LP-BM5 retrovirus mixture. Previous work from our laboratory has demonstrated that glial cells modulate antiviral T-cell effector responses through the programmed death (PD)-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Methods Using the MouseMet electronic von Frey system, we assessed hind-paw mechanical hypersensitivity in LP-BM5-infected wild-type (WT) and PD-1 KO animals. Using multi-color flow cytometry, we quantitatively assessed cellular infiltration and microglial activation. Using real-time RT-PCR, we assessed viral load, expression of IFN-γ, iNOS, and MHC class II. Using western blotting, we measured protein nitrosylation within the lumbar spinal cord (LSC) and dorsal root ganglion (DRG). Histochemical staining was performed to analyze the presence of CD3, ionized calcium binding adaptor molecule (Iba)-1, MHCII, nitrotyrosine, isolectin B4 (IB4) binding, and neurofilament 200 (NF200). Statistical analyses were carried out using graphpad prism. Results Hind-paw mechanical hypersensitivity observed in LP-BM5-infected animals was associated with significantly increased lymphocyte infiltration into the spinal cord and DRG. We also observed elevated expression of IFN-γ (in LSC and DRG) and MHC II (on resident microglia in LSC). We detected elevated levels of 3-nitrotyrosine within the LSC and DRG of LP-BM5-infected animals, an indicator of nitric oxide (NO)-induced protein damage. Moreover, we observed 3-nitrotyrosine in both small (IB4+) and large (NF200+) DRG sensory neurons. Additionally, infected PD-1 KO animals displayed significantly greater mechanical hypersensitivity than WT or uninfected mice at 4 weeks post-infection (p.i.). Accelerated onset of hind-paw hypersensitivity in PD-1 KO animals was associated with significantly increased infiltration of CD4+ and CD8+ T lymphocytes, macrophages, and microglial activation at early time points. Importantly, we also observed elevated levels of 3-nitrotyrosine and iNOS in infected PD-1 KO animals when compared with WT animals. Conclusions Results reported here connect peripheral immune cell infiltration and reactive gliosis with nitrosative damage. These data may help elucidate how retroviral infection-induced neuroinflammatory networks contribute to nerve damage and neuropathic pain.http://link.springer.com/article/10.1186/s12974-018-1107-7LP-BM5MAIDSNeuropathic painReactive gliosisNitrosylationPD-1 KO |
| spellingShingle | Priyanka Chauhan Wen S. Sheng Shuxian Hu Sujata Prasad James R. Lokensgard Nitrosative damage during retrovirus infection-induced neuropathic pain Journal of Neuroinflammation LP-BM5 MAIDS Neuropathic pain Reactive gliosis Nitrosylation PD-1 KO |
| title | Nitrosative damage during retrovirus infection-induced neuropathic pain |
| title_full | Nitrosative damage during retrovirus infection-induced neuropathic pain |
| title_fullStr | Nitrosative damage during retrovirus infection-induced neuropathic pain |
| title_full_unstemmed | Nitrosative damage during retrovirus infection-induced neuropathic pain |
| title_short | Nitrosative damage during retrovirus infection-induced neuropathic pain |
| title_sort | nitrosative damage during retrovirus infection induced neuropathic pain |
| topic | LP-BM5 MAIDS Neuropathic pain Reactive gliosis Nitrosylation PD-1 KO |
| url | http://link.springer.com/article/10.1186/s12974-018-1107-7 |
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