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Stress-Induced Neuroinflammation: Role of the Toll-Like Receptor-4 Pathway

  • Iciar Gárate
    Affiliations
    Department of Pharmacology, Universidad Complutense, Madrid, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain

    Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
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  • Borja Garcia-Bueno
    Correspondence
    Address correspondence to Borja García-Bueno, Ph.D., Complutense University of Madrid, Department de Pharmacology, School of Medicine, Madrid 28040, Spain
    Affiliations
    Department of Pharmacology, Universidad Complutense, Madrid, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain

    Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
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  • Jose Luis Muñoz Madrigal
    Affiliations
    Department of Pharmacology, Universidad Complutense, Madrid, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain

    Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
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  • Javier Rubén Caso
    Affiliations
    Department of Psychiatry, Universidad Complutense, Madrid, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain

    Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
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  • Luis Alou
    Affiliations
    Department of Medicine (Microbiology Area), Universidad Complutense, Madrid, Spain
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  • Marisa L. Gomez-Lus
    Affiliations
    Department of Medicine (Microbiology Area), Universidad Complutense, Madrid, Spain
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  • Juan Antonio Micó
    Affiliations
    Department of Neuroscience (Pharmacology & Psychiatry), University of Cádiz, Cádiz, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
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  • Juan Carlos Leza
    Affiliations
    Department of Pharmacology, Universidad Complutense, Madrid, Spain

    Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain

    Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
    Search for articles by this author

      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.

      Key Words

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