Nitrosative damage during retrovirus infection-induced neuropathic pain

Autor: Sujata Prasad, James R. Lokensgard, Shuxian Hu, Wen S. Sheng, Priyanka Chauhan
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Pathology
Programmed Cell Death 1 Receptor
Nitric Oxide Synthase Type II
Neuropathic pain
LP-BM5
lcsh:RC346-429
Mice
chemistry.chemical_compound
0302 clinical medicine
MAIDS
Dorsal root ganglion
Ganglia
Spinal
Leukocytes
Medicine
PD-1 KO
Mice
Knockout
Microglia
General Neuroscience
Nitrotyrosine
3. Good health
Cellular infiltration
medicine.anatomical_structure
Spinal Cord
Neurology
medicine.medical_specialty
Immunology
Interferon-gamma
03 medical and health sciences
Cellular and Molecular Neuroscience
Antigens
CD
Animals
RNA
Messenger
Neuroinflammation
lcsh:Neurology. Diseases of the nervous system
Protein nitrosylation
business.industry
Research
Nitrosylation
Histocompatibility Antigens Class II
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Retroviridae
030104 developmental biology
Peripheral neuropathy
chemistry
Neuralgia
business
Reactive gliosis
030217 neurology & neurosurgery
CD8
Retroviridae Infections
Zdroj: Journal of Neuroinflammation, Vol 15, Iss 1, Pp 1-16 (2018)
Journal of Neuroinflammation
ISSN: 1742-2094
DOI: 10.1186/s12974-018-1107-7
Popis: 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.
Databáze: OpenAIRE
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