Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

García‐Bueno, Borja; Gassó, Patricia; MacDowell, Karina S.; Callado, Luís F.; Mas, Sergi; Bernardo, Miquel; Lafuente, Amàlia; Meana, J. Javier; Leza, Juan C.

doi:10.1503/jpn.150195

Cited by 70 publications

(49 citation statements)

References 64 publications

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“…Moreover, MDD subjects died by suicide and under confirmed antidepressant treatment, as herein presented, should be considered more representative of resistant than standard depression. Although suicide was the cause of death for an important number of MDD subjects in the present study, opposite results for TLR-4 and NF-κB expression have been recently described in a schizophrenia population mainly dead by suicide [27]. Therefore, at least some of the changes herein observed in the postmortem brain of MDD subjects should be associated to depression and antidepressant treatment rather than to suicide behavior.…”

Section: Discussioncontrasting

confidence: 54%

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Martín-Hernández

Caso

Meana

et al. 2018

J Neuroinflammation

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BackgroundStudies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive.MethodsThis work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design.ResultsNo significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (− 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression.ConclusionData indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1294-2) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 54%

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Martín-Hernández

Caso

Meana

et al. 2018

J Neuroinflammation

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“…Although ours is the first study of TLRs in the postmortem brain of psychiatric patients (Pandey et al, 2014), TLRs have been studied in the blood of psychiatric patients. For example, Garcia-Bueno et al (2016) studied the protein expression of TLR4, MyD88, and NF-kB in the blood and PFC of patients with schizophrenia. They found an increase in the protein expression of TLR4 in the PFC of schizophrenic patients compared with normal control subjects.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors

Pandey

Rizavi

Bhaumik

et al. 2019

Brain, Behavior, and Immunity

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Abnormalities of Toll-like receptors (TLRs) have been implicated in the pathophysiology of depression and suicide. Interactions of TLRs with pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) initiate signaling through myeloid differentiation primary response-88 (MyD88) and produce cytokines through the activation of the transcription factor nuclear factor kappa beta (NF-kB). We have earlier shown an increase in the protein and mRNA expression of TLR3 and TLR4 in the prefrontal cortex (PFC) of depressed suicide (DS) subjects compared with normal control (NC) subjects. To examine if other TLRs are altered in postmortem brain, we have now determined the protein and mRNA expression of other TLRs (TLR1, TLR2, TLR5, TLR6, TLR7, TLR8, TLR9 and TLR10) in the PFC of DS, depressed non-suicide (DNS), non-depressed suicide (NDS) and NC subjects. We determined the protein expression by Western blot and mRNA expression levels by real-time PCR (qPCR) in the PFC of 24 NC, 24 DS, 12 DNS and 11 NDS subjects. Combined with our previous study of TLR3 and TLR4, we found that the protein expression of TLR2, TLR3, TLR4, TLR6 and TLR10, and mRNA expression of TLR2 and TLR3 was significantly increased in the DS group compared with NC group. This study demonstrated that certain specific TLRs are altered in DS subjects, and hence those TLRs may be appropriate targets for the development of therapeutic agents for the treatment of suicidal behavior.

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“…Three original studies [8,13,21] and one metaanalysis [27] have found elevated mRNA expressions of several pro-inflammatory cytokines and Toll-like receptors in post-mortem brains of individuals with schizophrenia. Moreover, as it was mentioned above, Hayes et al [14] found higher levels of IL-8 in the CSF of psychosis individuals compared to healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

The effect of excess weight on circulating inflammatory cytokines in drug-naïve first-episode psychosis individuals

Ruíz

Riesco-Dávila

Foz

et al. 2018

J Neuroinflammation

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Background: Low-grade inflammation has been repeatedly associated with both excess weight and psychosis. However, no previous studies have addressed the direct effect of body mass index (BMI) on basal serum cytokines in individuals with first-episode psychosis (FEP). Objectives: The aim of this study is to analyze the effect of BMI on basal serum cytokine levels in FEP patients and control subjects, separating the total sample into two groups: normal-weight and overweight individuals. Methods: This is a prospective and open-label study. We selected 75 FEP patients and 75 healthy controls with similar characteristics to patients according to the following variables: sex, age, and cannabis and tobacco consumption. Both controls and patients were separated into two groups according to their BMI: subjects with a BMI under 25 were considered as normal weight and those with a BMI equal to or more than 25 were considered as overweight. Serum levels of 21 cytokines/chemokines were measured at baseline using the Human High Sensitivity T Cell Magnetic Bead Panel protocol from the Milliplex® Map Kit. We compared the basal serum levels of the 21 cytokines between control and patient groups according to their BMI. Results: In the normal-weight group, IL-8 was the only cytokine that was higher in patients than in the control group (p = 0.001), whereas in the overweight group, serum levels of two pro-inflammatory cytokines (IL-6, p = 0.000; IL-1β, p = 0.003), two chemokines (IL-8, p = 0.001; MIP-1β, p = 0.001), four Th-1 and Th-2 cytokines (IL-13, p = 0.009; IL-2, p = 0.001; IL-7, p = 0.001; IL-12p70, p = 0.010), and one Type-3 cytokine (IL-23, p = 0.010) were higher in patients than in controls. Conclusions: Most differences in the basal serum cytokine levels between patients and healthy volunteers were found in the overweight group. These findings suggest that excess weight can alter the homeostasis of the immune system and therefore may have an additive pro-inflammatory effect on the one produced by psychosis in the central nervous system.

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Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

Cited by 70 publications

References 64 publications

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors

The effect of excess weight on circulating inflammatory cytokines in drug-naïve first-episode psychosis individuals

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