Early-life stress and inflammatory cytokines in psychoses: from bench to community-based research

Author(s)

Fabiana Maria das Graças Corsi Zuelli

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-02-22

Examining board members

Cristina Marta Del Ben; Elisa Macedo Brietzke; João Pereira Leite; Christie Ramos Andrade Leite Panissi

• Advisor: Cristina Marta Del Ben

Abstract

Epidemiological studies suggest an interaction between biological and environmental factors in the development of psychoses and early-life stress constitutes an important risk factor. Recently, significant attention has been given to the inflammatory hypothesis of psychoses; yet, investigations on the relationship between early-life stress, inflammation and psychoses are scarce. We aimed to investigate associations between early-life stress and inflammatory cytokines in a preclinical model of schizophrenia (post-weaning social isolation), as well as in a clinical study of first-episode psychosis (FEP) patients, unaffected siblings and communitybased controls. i) Preclinical study: male Wistar rats (n=20) were submitted to post-weaning social isolation for 10 weeks. After that, rats were assessed for locomotion in the open field (20 minutes) and euthanised for cytokines measurement. Cytokines protein and gene expression (IL-6, TNF-?, IL-10) were measured in the peripheral blood as well as in the prefrontal cortex and hippocampus. Social isolated rats had decreased IL-10 protein and gene expression in the blood and decreased IL-10 protein in the hippocampus. We also observed reduced IL-6 protein and gene expression in the prefrontal cortex. IL-10 hippocampal levels were negatively correlated with hyperlocomotion in the open field. Although the unexpected decrease in IL-6 and unchanged TNF-? levels contrast to the expected pro-inflammatory phenotype, this may suggest that reduced anti-inflammatory signalling may be critical for eliciting abnormal behaviour in adulthood. Altogether, these results suggest that prolonged early-life adverse events reduce the anti-inflammatory cytokine IL-10 and this is translated from blood-to-brain. ii) Clinical study: we recruited 114 first-episode psychosis (FEP) patients, 57 unaffected siblings of FEP patients, and 251 community-based controls. Cytokines plasma levels (IL-1?, TNF-?, IFN-?, IL-6, IL-4, IL-10 and TGF-?) were measured and differences across the three groups analysed after controlling for age, gender, body mass index and tobacco smoking. Childhood maltreatment was measured by the Childhood Trauma Questionnaire and plasma cytokines by multiplex. FEP had significantly higher levels of IL-6, TNF-?, IL-10 and TGF-? when compared with controls, and also higher levels of IL-1?, IL-6, TNF-?, and IL-10 whencompared with their siblings. Siblings presented decreased IL-1? when compared with controls. Physical childhood abuse was associated with increased levels of TGF-? in FEP. Experience of childhood maltreatment, specifically physical abuse, may contribute as a long-term immune priming for the TGF-? pathway in both patients and community-based controls. Normal or reduced levels of cytokines in siblings represent possibly a protective factor. In conclusion, the results from our preclinical and clinical study do not support associations between enhanced pro-inflammatory cytokines and early-life stress in psychoses. The blunted inflammatory profile found in chronic pwSI may represent stress-exposure during the latter stages of the disorder, contrasting the high inflammatory profile during earlier stages. The type and duration of adverse experiences may impact differently on the levels of inflammatory markers across different populations. Moreover, it is highly possible that the inflammatory profile reported in our clinical population arise from cumulative risk factors that will need to be explored in future investigations. (AU)

• FAPESP's process: 16/12195-9 - Impact of early life stress in the inflammatory profile of first episode of psychosis (FEP) patients and in the animal model of post-weaning social isolation
• Grantee: Fabiana Maria das Graças Corsi Zuelli
• Support Opportunities: Scholarships in Brazil - Master