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Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis
- Source :
- PLoS ONE, PLoS ONE, Vol 6, Iss 4, p e18190 (2011)
- Publication Year :
- 2011
- Publisher :
- Public Library of Science (PLoS), 2011.
-
Abstract
- Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects beyond addiction. However, the underlying mechanism by which microglia in response to opioids remains largely unknown. Here we show that morphine induces the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, TLR9 deficiency significantly inhibited morphine-induced apoptosis in microglia. Similar results were obtained when endogenous TLR9 expression was suppressed by the TLR9 inhibitor CpGODN. Inhibition of p38 MAPK by its specific inhibitor SB203580 attenuated morphine-induced microglia apoptosis in wild type microglia. Morphine caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type microglia, but not in TLR9 deficient microglia. In addition, morphine treatment failed to induce an increased levels of phosphorylated p38 MAPK and MAP kinase kinase 3/6 (MKK3/6), the upstream MAPK kinase of p38 MAPK, in either TLR9 deficient or µ-opioid receptor (µOR) deficient primary microglia, suggesting an involvement of MAPK and µOR in morphine-mediated TLR9 signaling. Moreover, morphine-induced TLR9 expression and microglia apoptosis appears to require μOR. Collectively, these results reveal that opioids prime microglia to undergo apoptosis through TLR9 and µOR as well. Taken together, our data suggest that inhibition of TLR9 and/or blockage of µOR is capable of preventing opioid-induced brain damage.
- Subjects :
- Central Nervous System
MAPK/ERK pathway
Pyridines
Neuroimmunology
Oligonucleotides
lcsh:Medicine
Apoptosis
Signal transduction
p38 Mitogen-Activated Protein Kinases
Mice
Molecular cell biology
0302 clinical medicine
Signaling in Cellular Processes
lcsh:Science
Receptor
Immune Response
Apoptotic Signaling
Mice, Knockout
Neurons
0303 health sciences
Multidisciplinary
Morphine
Microglia
Imidazoles
Signaling cascades
Innate Immunity
3. Good health
Cell biology
Analgesics, Opioid
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Neurology
Cytokines
Medicine
Cellular Types
medicine.symptom
Research Article
medicine.drug
MAPK signaling cascades
Immune Cells
p38 mitogen-activated protein kinases
Immunology
Antigen-Presenting Cells
Neurophysiology
chemical and pharmacologic phenomena
Inflammation
Biology
Signaling Pathways
Immune Activation
03 medical and health sciences
Apoptotic signaling cascade
medicine
Animals
Pain Management
030304 developmental biology
lcsh:R
Immunity
Wild type
TLR9
Immune Defense
Immunologic Subspecialties
Immunity, Innate
Opioid
Toll-Like Receptor 9
Immune System
Cancer research
lcsh:Q
CpG Islands
Molecular Neuroscience
Neuroscience
030215 immunology
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....949672f4bc03e40bc971175b85b6dd8c