16 de junio de 2013

Stress como inductor de neuroinflamación

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
  • ,
  • Borja Garcia-Bueno

      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
    • Corresponding Author InformationAddress correspondence to Borja García-Bueno, Ph.D., Complutense University of Madrid, Department de Pharmacology, School of Medicine, Madrid 28040, Spain
  • ,
  • 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
  • ,
  • 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
  • ,
  • Luis Alou

      Affiliations

    • Department of Medicine (Microbiology Area), Universidad Complutense, Madrid, Spain
  • ,
  • Marisa L. Gomez-Lus

      Affiliations

    • Department of Medicine (Microbiology Area), Universidad Complutense, Madrid, Spain
  • ,
  • 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
  • ,
  • Juan Carlos Leza

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.