Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to Borrelia burgdorferi lipoproteins.
Lyme borreliosis, which is prevalent both in the US and in Europe, is an infectious disease that may cause local inflammation in numerous organs. We have hypothesized that, as with some neurodegenerative diseases, the pathogenesis of the neurocognitive deficiencies associated with Lyme neuroborreliosis of the central nervous system also has an inflammatory component. Dysregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage. Mitogen-activated protein kinases (MAPK) play a key role in the regulation of neuronal development, growth, and survival, as well as that of pro-inflammatory cytokine production. As a model, we explored the possibility that MAPK-mediated lipoprotein-induced apoptosis and gliosis of rhesus monkey astrocytes stimulated in vitro. Lipoproteins are the key inflammatory molecule type of Borrelia burgdorferi, the spirochete that causes Lyme disease, and we had previously shown that lipoprotein-induced TNF-alpha production in astrocytes caused astrocyte apoptosis, and IL-6 enhanced proliferation of these cells. Lipoproteins readily activated p38 and Erk1/2 MAPK, thus enlisting these pathways among the kinase pathways that spirochetes may address as they invade the central nervous system. We also investigated whether specific inhibition of p38 and Erk1/2 MAPK would inhibit TNF-alpha and IL-6 production and thus astrocyte apoptosis, and proliferation, respectively. Lipoprotein-stimulated IL-6 production was unaffected by the MAPK inhibitors. In contrast, inhibition of both p38 and Erk1/2 significantly diminished TNF-alpha production, and totally abrogated production of this cytokine when both MAPK pathways were inhibited simultaneously. MAPK inhibition thus may be considered as a strategy to control inflammation and apoptosis in Lyme neuroborreliosis.
Ramesh
Geeta
G
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433, USA.
Philipp
Mario T
MT
D000818:Animals; D000954:Antigens, Surface / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology*; D001428:Bacterial Vaccines; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology*; D020852:Lyme Neuroborreliosis / Q000201:enzymology / Q000473:pathology*; D008253:Macaca mulatta; D020928:Mitogen-Activated Protein Kinases / Q000145:classification / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008074:Lipoproteins; C072045:OspA protein; D014409:Tumor Necrosis Factor-alpha; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D020928:Mitogen-Activated Protein Kinases; D003545:Cysteine