Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis.
Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is activated by thrombin and is implicated in the pathogenesis of inflammation. Although PAR-1 is expressed on immunocompetent cells within the brain such as astrocytes, little is known about its role in the pathogenesis of inflammatory brain diseases. Herein, we investigated PAR-1 regulation of brain inflammation by stimulating human astrocytic cells with thrombin or the selective PAR-1-activating peptide. Activated cells expressed significantly increased levels of IL-1 beta, inducible NO synthase, and PAR-1 mRNA. Moreover, supernatants of these same cells were neurotoxic, which was inhibited by an N-methyl-D-aspartate receptor antagonist. Striatal implantation of the PAR-1-activating peptide significantly induced brain inflammation and neurobehavioral deficits in mice compared with mice implanted with the control peptide or saline. Since HIV-related neurological disease is predicated on brain inflammation and neuronal injury, the expression of PAR-1 in HIV encephalitis (HIVE) was investigated. Immunohistochemical analysis revealed that PAR-1 and (pro)-thrombin protein expression was low in control brains, but intense immunoreactivity was observed on astrocytes in HIVE brains. Similarly, PAR-1 and thrombin mRNA levels were significantly increased in HIVE brains compared with control and multiple sclerosis brains. These data indicated that activation and up-regulation of PAR-1 probably contribute to brain inflammation and neuronal damage during HIV-1 infection, thus providing new therapeutic targets for the treatment of HIV-related neurodegeneration.
Boven
Leonie A
LA
Neuroscience Research Group, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Vergnolle
Nathalie
N
Henry
Scot D
SD
Silva
Claudia
C
Imai
Yoshinori
Y
Holden
Janet
J
Warren
Kenneth
K
Hollenberg
Morley D
MD
Power
Christopher
C
D015526:AIDS Dementia Complex / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002474:Cell-Free System / Q000502:physiology; D003342:Corpus Striatum / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D004343:Drug Implants; D005333:Fetus; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010455:Peptides / Q000008:administration & dosage / Q000502:physiology; D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D018179:Receptors, Thrombin / Q000008:administration & dosage / Q000819:agonists / Q000096:biosynthesis* / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D004343:Drug Implants; D007375:Interleukin-1; D009498:Neurotoxins; D010455:Peptides; D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate; D018179:Receptors, Thrombin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013917:Thrombin