Gárate, IciarGarcía Bueno, BorjaMuñoz Madrigal, José LuisCaso Fernández, Javier RubénAlou Cervera, LuisGómez-Lus Centelles, María LuisaMicó, Juan AntonioLeza Cerro, Juan Carlos2024-07-232024-07-232013-01Gárate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Micó JA, Leza JC. Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway. Biol Psychiatry. 2013 Jan 1;73(1):32-430006-322310.1016/j.biopsych.2012.07.005https://hdl.handle.net/20.500.14352/107061Background: 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.engjournal articlehttps://doi.org/10.1016/j.biopsych.2012.07.005https://www.sciencedirect.com/science/article/pii/S0006322312005999restricted access611.02615Antibiotic decontaminationbacterial translocationinnate immunityneuroinflammationstressTLR-4 signalingFarmacología (Medicina)Microbiología médica3209 Farmacología2414 Microbiología