Lentivirus infection causes neuroinflammation and neuronal injury in dorsal root ganglia: pathogenic effects of STAT-1 and inducible nitric oxide synthase.
Distal sensory polyneuropathy (DSP) is currently the most common neurological complication of HIV infection in the developed world and is characterized by sensory neuronal injury accompanied by inflammation, which is clinically manifested as disabling pain and gait instability. We previously showed that feline immunodeficiency virus (FIV) infection of cats caused DSP together with immunosuppression in cats, similar to that observed in HIV-infected humans. In this study, we investigated the pathogenic mechanisms underlying the development of FIV-induced DSP using feline dorsal root ganglia (DRG) cultures, consisting of neurons, Schwann cells, and macrophages. FIV-infected cultures exhibited viral Ags (p24 and envelope) in macrophages accompanied by neuronal injury, indicated by neurite retraction, neuronal loss and decreased soma size, compared with mock-infected (control) cultures. FIV infection up-regulated inducible NO synthase (iNOS), STAT-1, and TNF-alpha mRNA levels in DRG cultures. Increased STAT-1 and iNOS mRNA levels were also observed in DRGs from FIV-infected animals relative to mock-infected controls. Similarly, immunolabeling studies of DRGs from FIV-infected animals showed that macrophages were the principal sources of STAT-1 and iNOS protein production. The iNOS inhibitor aminoguanidine reduced nitrotyrosine and protein carbonyl levels, together with preventing neuronal injury in FIV-infected DRG cultures. The present studies indicate that FIV infection of DRGs directly contributes to axonal and neuronal injury through a mechanism involving macrophage immune activation, which is mediated by STAT-1 and iNOS activation.
Zhu
Yu
Y
Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.
Jones
Gareth
G
Tsutsui
Shigeki
S
Opii
Wycliffe
W
Liu
Shuhong
S
Silva
Claudia
C
Butterfield
D Allan
DA
Power
Christopher
C
D000818:Animals; D002415:Cats; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D005727:Ganglia, Spinal / Q000201:enzymology / Q000473:pathology* / Q000821:virology*; D006146:Guanidines / Q000494:pharmacology; D016089:Immunodeficiency Virus, Feline / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000821:virology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D011115:Polyneuropathies / Q000201:enzymology / Q000473:pathology / Q000821:virology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005609:Free Radicals; D006146:Guanidines; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine