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

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

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J Psychiatry Neurosci 2016;41(3):E46-E55

Borja García-Bueno, PhD*; Patricia Gassó, PhD*; Karina S. MacDowell, PhD; Luis F. Callado, PhD, MD; Sergi Mas, PhD; Miguel Bernardo, PhD, MD; Amalia Lafuente, PhD; J. Javier Meana, PhD, MD; Juan C. Leza, PhD, MD


Background: Alterations in the innate immune/inflammatory system may underlie the pathophysiology of schizophrenia, but we do not understand the mechanisms involved. The main agents of innate immunity are the Toll-like receptors (TLRs), which detect molecular patterns associated with damage and pathogens. The TLR first reported was TLR4, and it is still the most studied one.

Methods: We aimed to describe putative modifications to the TLR4 proinflammatory pathway using 2 different strategies in 2 cohorts of patients with schizophrenia and matched controls: 1) quantification of protein and mRNA expression in postmortem prefrontal cortex samples from 30 patients with schizophrenia and 30 controls, and 2) identification of single nucleotide polymorphisms associated with the risk of schizophrenia using whole blood samples from 214 patients with schizophrenia and 216 controls.

Results: We found evidence of alterations in the expression of the initial elements of the TLR4 signalling pathway (TLR4, Myeloid differentiation primary response gene 88 [MyD88] and nuclear factor-κ B [NF-κB]) in the PFC of patients with schizophrenia. These alterations seem to depend on the presence/absence of antipsychotic treatment at death. Moreover, a polymorphism within the MyD88 gene was significantly associated with schizophrenia risk.

Limitations: The use of 2 different approaches in 2 different cohorts, the lack of a complementary neuropsychiatric group, the possible confounding effects of antipsychotic treatment and suicide are the main limitations of our study.

Conclusion: The evidence from this dual approach suggests there is an altered innate immune response in patients with chronic schizophrenia in which the TLR4 proinflammatory pathway could be affected. Improved understanding of the stimuli and mechanisms responsible for this response could lead to improved schizophrenia treatment and better control of the side effects of current antipsychotics.

*These authors contributed equally to this work.

Submitted May 26, 2015; Revised Nov. 2, 2015; Accepted Dec. 21, 2015; Early-released Apr. 12, 2016

Acknowledgements: This work was supported by the Instituto de Salud Carlos III (FIS 10/00123 and 13/1102); MINECO-FEDER Funds (SAF2013–48586-R); and regional authorities of Catalonia via the Secretaria d’Universitats i Recerca, Departament d’Economia i Coneixement (2014SGR441). The work was partly developed at the Centro Esther Koplowitz (Barcelona), CIBERSAM, and the Foundation Santander- UCM (GR 58/08). BGB is a Ramón y Cajal fellow (MINECO). The authors provide full disclosure of any and all biomedical financial interests and declare that there are no conflicts of interest. The authors thank staff of the Basque Institute of Legal Medicine, Bilbao for their cooperation in this work.

Affiliations: From the CIBERSAM. ISCIII, Spain (García-Bueno, MacDowell, Callado, Mas, Bernardo, Lafuente, Meana, Leza); the Department of Pharmacology, School of Medicine, Complutense University & Instituto de Investigación Hospital 12 de Octobre (Imas12). Madrid (García-Bueno, MacDowell, Leza); the Department of Anatomic Pathology, Pharmacology and Microbiology. School of Medicine, University of Barcelona, Barcelona (Gassó, Mas, Lafuente); the Department of Pharmacology, University of Basque Country UPV/EHU and Bio- Cruces Institute, Bizkaia (Callado, Meana); the IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona (Gassó, Mas, Bernardo, Lafuente); and the Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology, University of Barcelona (Bernardo).

Competing interests: None declared.

Contributors: B. García-Bueno, P. Gassó and J. Leza designed the study. P. Gassó, A. Lafuente, K. MacDowell, S. Mas and J. Meana acquired the data, which B. García-Bueno, P. Gassó, L. Callado, M. Bernardo, A. Lafuente, J. Meana and J. Leza analyzed. B. García- Bueno, P. Gassó and J. Leza wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150195

Correspondence to: J.C. Leza, Department de Pharmacology, School of Medicine, Complutense University of Madrid; jcleza@med.ucm.es