AbstractInterferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the mechanisms underlying these effects are not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in depressed versus non-depressed patients. There is indeed evidence for blood factors, including IFN-α, to penetrate the blood brain barrier and modulate different signalling in the brain. Using a human hippocampal progenitor cells (HPCs) model firstly I examined the damaging effects of IFN-α on neurogenesis and apoptosis; secondly I investigated the effect of serum from depressed and non-depressed patients with HCV on neurogenesis and apoptosis across disease progression at baseline (before receiving IFN-α, treatment week (TW) 0) and after four weeks (TW4) of IFN-α treatment.
In the in vitro study with IFN-α I show that the cytokine decreased neurogenesis and increased apoptosis. Moreover, IFN-α increased the expression of IFN-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and levels of interleukin-6 (IL-6), via activation of STAT1. Like IFN-α itself, combination treatment with ISG15, USP18 and IL-6 was able to reduce neurogenesis and to enhance apoptosis, via further downstream activation of STAT1. Using transcriptomic analyses, I also showed that IFN-α regulated pathways involved in oxidative stress and immune response.
In the in vitro study with serum samples from IFN-α-treated HCV patients I show that a high percentage of apoptotic cells observed upon treatment of HPCs with TW0 serum, and a low percentage of neurogenic cells observed upon treatment with TW4 serum was predictive of later depression. Furthermore, a low increase in the percentage of neurogenic cells between TW0 and TW4 was also predictive of IFN-α-induced depression, proposing this model as the best predictive one.
In conclusion, both studies provide further insights on the association between inflammation-dependent regulation of neurogenesis and later development of neuropsychiatric conditions.
Statement of Contribution
Dr Anna Cattaneo performed the analysis of gene expression microarray (section 2.2.5). Recruitment of patients as well as blood processing (serum and plasma separation) were performed by Miss Alessandra Borsini, Dr Nilay Hepgul, Miss Alice Russell and Miss Zuzanna Zajkowska. All other experiments were conducted by Miss Alessandra Borsini, under the supervision of Dr Patricia Zunszain, Dr Sandrine Thuret and Prof. Carmine Pariante. The human hippocampal progenitor cells were kindly provided by Professor Jack Price, on behalf of ReNeuron.
|Date of Award
|Patricia Zunszain (Supervisor), Sandrine Thuret (Supervisor) & Carmine Pariante (Supervisor)