Epigenetic, neuroplasticity and inflammatory biomarkers of major depression and treatment response in immune cells
- Autores: Ainhoa Garayo Larrea
- Directores de la Tesis: Rosa Maria Tordera (dir. tes.), Amaya Azqueta Oscoz (dir. tes.)
- Lectura: En la Universidad de Navarra ( España ) en 2024
- Idioma: español
- Tribunal Calificador de la Tesis: María Jesús Sanz Ferrando (presid.), Diego Óscar Alignani (secret.), Vanessa Valdiglesias (voc.), Elena Puerta (voc.), Guadalupe Rivero Calera (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Dadun
- Resumen
Through biomarkers, personalized medicine aims to optimize the treatment for a disease in each person from the first day. During the past decades, depression has been associated to synaptic plasticity deficits and neuronal atrophy, often accompanied by reduced neurotrophin levels. Additionally, neuroinflammation and oxidative damage has been observed in major depression (MD). Interestingly, epigenetic mechanisms in which some histone deacetylases (HDACs) are involved, could play a pivotal role in triggering both neuroinflammation and neuroplasticity failure. In particular, altered expression of specific HDACs, are associated with depressive-like behavior, suppression of the brain derived neurotrophic factor (BDNF), and the promotion of inflammation in the brain. In parallel, clinical studies describe alterations of several HDACs and increased expression of some inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) of MD patients.
Objectives: The general aim of this thesis is to identify biological parameters that can serve as peripheral biomarkers of MD and clinical response. Particularly, this study examined the influence of MD and clinical response on the regulation of several HDACs, especially HDAC5, the neuroplasticity gene BDNF and genes linked to inflammation in monocytes and T-cells. In addition, this study has evaluated the influence of MD on PBMCs vulnerability to DNA damage.
Methods: A team of psychiatrists from different hospitals and health care centers from Pamplona (Navarra) recruited 47 MD patients (MADRS≥20) and age and sex matched healthy controls (HC). Among the MD patients, 41 patients participated in a longitudinal study. Blood samples (25 mL, heparin tubes) were obtained from each participant at enrolment and at a subsequent medical visit. MD patients were classified according to clinical response in responders and non-responder MD patients. From each blood sample, monocytes (classic, intermediate and non-classic) and T-cells (CD3+) were isolated by fluorescence activated cell sorter (FACS).
Results: MD upregulated HDAC5 mRNA in classic and intermediate monocytes as well as in T-cells and this upregulation was reverted in responder MD patients. Further, MD increased nuclear and cytoplasmic localizations of HDAC5 and SIRT6 respectively. BDNF mRNA expression was downregulated in intermediate monocytes and in T-cells of MD patients and again responder patients recovered a normal expression of BDNF similar to HC participants. On the other hand, MD upregulated IL6 and ADRB2 mRNA, the gene encoding β2 adrenoceptor, in classic monocytes. While IL6 was attenuated by clinical response, high levels of ADRB2 were maintained in both responder and non-responder MD patients. Further, while LPS enhanced NF-ΚB p65 nuclear accumulation as well as HDAC5 and H3K9ac immunofluorescence in monocytes of HC, MD monocytes failed to respond to this acute inflammatory stimulus since no changes in any of these proteins were observed. Notably, a recovery of acute immune response was observed in monocytes of responder MD patients. Finally, despite MD patients did not exhibit higher levels of strand breaks or oxidized DNA compared to HC, H2O2 induced higher % DNA in tail in PBMCs from MD patients compared to controls.
Conclusions: Altogether, these observations support the notion that immune cells of MD patients show a low-grade inflammatory phenotype in which the epigenetic enzymes could be involved. Moreover, this proinflammatory environment could heighten immune cell DNA vulnerability to oxidative agents.
