Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway.
BACKGROUND
Stressful challenges are associated with variations in immune parameters, including increased innate immunity/inflammation. Among possible mechanisms through which brain monitors peripheral immune responses, toll-like receptors (TLRs) recently emerged as the first line of defense against invading microorganisms. Their expression is modulated in response to pathogens and other environmental stresses.


METHODS
Taking into account this background, the present study aimed to elucidate whether the toll-like receptor-4 (TLR-4) signaling pathway is activated after repeated restraint/acoustic stress exposure in mice prefrontal cortex (PFC), the potential regulatory mechanism implicated (i.e., bacterial translocation), and its role in conditions of stress-induced neuroinflammation, using a genetic strategy: C3H/HeJ mice with a defective response to lipopolysaccharide stimulation of TLR-4.


RESULTS
Stress exposure upregulates TLR-4 pathway in mice PFC. Stress-induced inflammatory nuclear factor κB activation, upregulation of the proinflammatory enzymes nitric oxide synthase and cyclooxygenase type 2, and cellular oxidative/nitrosative damage are reduced when the TLR-4 pathway is defective. Conversely, TLR-4 deficient mice presented higher levels of the anti-inflammatory nuclear factor peroxisome proliferator activated receptor-gamma after stress exposure than control mice. The series of experiments using antibiotic intestinal decontamination also suggest a role for bacterial translocation on TLR-4 activation in PFC after stress exposure.


CONCLUSIONS
Taken together, all the data presented here suggest a bifunctional role of TLR-4 signaling pathway after stress exposure by triggering neuroinflammation at PFC level and regulating gut barrier function/permeability. Furthermore, our data suggest a possible protective role of antibiotic decontamination in stress-related pathologies presenting increased intestinal permeability (leaky gut) such as depression, showing a potential therapeutic target that deserves further consideration.
Department of Pharmacology, Universidad Complutense, Madrid, Spain.
Iciar
I
Gárate
Borja
B
Garcia-Bueno
Jose Luis Muñoz
JL
Madrigal
Javier Rubén
JR
Caso
Luis
L
Alou
Marisa L
ML
Gomez-Lus
Juan Antonio
JA
Micó
Juan Carlos
JC
Leza
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D007070:Immunoglobulin A / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D017397:Prefrontal Cortex / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism / Q000502:physiology*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D007070:Immunoglobulin A; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D051197:Toll-Like Receptor 4; D000099231:Lipopolysaccharide-Binding Protein; C493487:Tlr4 protein, mouse