Dysregulation of the immune response dynamics in a preclinical model of Anorexia Nervosa: evidence of a periphery-to-brain crosstalk

Background Anorexia Nervosa (AN) is a severe psychiatric disorder characterized by extreme emaciation whose root-based molecular mechanisms are unknown and treatments elusive. Our hypothesis is that a dysregulation of the immune system together with the hyperactivation of the hypothalamic–pituitary–adrenal axis (HPA) axis, induced by loss of body weight and hyperactivity, may act as a fil rouge establishing a dysfunctional neuro-immune-metabolic axis potentially critical in AN long-lasting maintenance. Methods We used the activity-based anorexia (ABA) rat model by exposing adolescent female rats to food restriction and wheel exercise. Results ABA rats showed altered levels of circulating and medullary-resident innate immune cells both in the acute phase and following bodyweight recovery. Together, ABA rats in their acute condition showed elevated corticosterone levels, a critical regulator of stress and immune response, while reduced after recovery. Moreover, the acute AN phenotype induced hippocampal neuroinflammation and boosted glucocorticoid receptor (GR) translocation in the ventral hippocampus of ABA rats, which, in turn, evoked microglial hyperactivation after recovery. Interestingly, mifepristone, a GR non-selective antagonist, blunted ABA rat’s hyperactivity and restored, at least partially, the molecular signatures induced by the AN phenotype. Conclusion These results suggest that AN-induced alterations in immune response cause endurable central dysfunctions throughout the activation of a late hippocampal microglial response, critical in vulnerable phenotypes, which may involve corticosterone as driver. This may represent a potential mechanism underpinning the increased risk of infections and the severity of the AN phenotype in the long range. Sponsored by Cariplo Foundation (2023-1003)