Work Package 4
Inflammatory mechanisms in the context of gene x environment interactions in affective disorders
PD Dr. Judith Alferink1, Prof. Dr. Carsten Culmsee2, Prof. Dr. Holger Garn³
1University of Münster, Department of Psychiatry and Psychotherapy
2University of Marburg, Institute for Pharmacology and Clinical Pharmacy
3University of Marburg, Institue of Laboratory Medicine and Pathobiochemistry
Immune dysregulations represent a longstanding enigma in the pathophysiology of affective disorders (ADs). However, the underlying mechanisms of GxE interactions in AD and associated immune alterations are largely unknown. Therefore, longitudinal studies are needed in animal models and in humans exposed to GxE interactions to gain novel insights into immune signatures and their prognostic and functional significance in AD. Our animal studies in the 1st funding period revealed altered immune responses and epigenetic regulations in Cacna1c+/- versus WT rats in response to social isolation and environmental/social enrichment. Further, microglial activation and bioenergetic capacities to an immune stimulus were abrogated under Cacna1c+/- conditions, suggesting an overall reduced immune capacity associated with this risk gene. In analogy to the rat model, our human studies point toward reduced cytokine-producing and bioenergetic capacities of stimulated immune cells from the peripheral blood of MDD patients compared to healthy individuals. Further, we established a cellular large-scale multi-parameter flow cytometry screen at the single cell level. Cell-type specific characterisations are of major importance, since overlapping cytokine profiles of immune cells may modulate the overall outcome of inflammatory responses in AD and, importantly, immune signatures of specific cell subsets may harbour prognostic potential. Our current findings formed the basis for the working hypotheses, probing altered immune signatures in humans and rodents exposed to GxE risks for AD. We hypothesise that specific immune signatures characterise particular disease phases in AD and may serve as prognostic markers in humans. We address this hypothesis in the 2nd funding period in a longitudinal study in MDD patients and in healthy participants of the MACS cohort, including those with familial genetic risk and exposure to early life stress (childhood maltreatment). Further, we will investigate whether the altered immune signatures identified in patients are also associated with GxE risk interaction in the Cacna1c+/- rat model in conditions of social isolation, enriched environment, and an additional immune stimulus. We hypothesise that heterozygous Cacna1c risk gene expression may affect peripheral immune signatures and neuroinflammatory responses associated with AD-related behavioural changes in rats subjected to environmental risk and/or an external inflammatory stimulus. This translational approach of Work Package 4 will provide new insights into altered signatures in subsets of peripheral immune cells in animals and humans exposed to GxE risk factors for AD. The identified immune signatures may serve as biomarkers in different phases of AD and in humans at risk. In parallel, the rat model and derived microglial cultures will allow for mechanistic analyses of interactions between the altered peripheral immune capacity and neuro-inflammatory responses in defined GxE risk settings.