Effects of chronic inflammation on the immune system and central nervous system.

• Applicant: Dr. Justus Ninnemann
• Subject Area: Biological Psychiatry ; Experimental Models for the Understanding of Nervous System Diseases ; Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533590976

The brain senses inflammatory signals upon infection and responds by inducing sickness behaviour, which is characterized by fever, lethargy, social withdrawal and reduced appetite. This coordinated response of the immune system and the brain may represent an efficient strategy to control infection at the population level. Proinflammatory cytokines such as interleukin (IL)-6, tumour necrosis factor (TNF), IL-1beta and IL-18 are detected by the nervous system either through sensory nerve fibers located at peripheral sites of inflammation or directly by neuronal, myeloid and stroma cells in the circumventricular organs (CVOs) of the brain. Sensing of inflammatory mediators can activate various neuronal circuits, among them the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of corticosterone (mouse)/ cortisol (human) (CS) into the blood. This CS response suppresses the immune reaction through the activation of the glucocorticoid receptor (GR) expressed by most immune cells to prevent runaway immune responses. As a consequence, CS regulates the development of thymic T cells, the maturation of B cells in the bone marrow (BM), the release of granulocytes into the blood, and cytokine production by dendritic cells (DCs) and macrophages. Thus, detection of inflammation allows the brain to coordinate immune, metabolic and behavioural responses to infection in order to optimize survival. However, the effects of a chronic exposure to inflammation on these neuronal circuits and subsequent immune responses remain poorly characterized. The presence of inflammatory cytokines, their detection by the brain, the subsequent behavioural responses and dysregulation of the HPA axis are found to be associated with the development of psychiatric disorders. Patients suffering from depression display increased serological levels of TNF, IL-6, and IL-18. Additionally, a hyperactive HPA axis is a hallmark of major depressive disorder (MDD). In mice, depressive-like behaviour can be induced by inflammatory stimuli such as the bacterial endotoxin lipopolysaccharide (LPS). Although the association between inflammatory conditions and the development of mood disorders is well established, the underlying mechanisms remain unknown. The work presented in this proposal aims to determine the effects of chronic inflammation on the interplay between the immune system, the recruited neuronal pathways in the brain and the associated development of mood disorders.

• DFG Programme: WBP Fellowship
• International Connection: France
• Host: Professor Dr. Gérard Eberl