Blood IL-6 is a critical trigger of depressive symptoms in a mouse model for human atopic dermatitis.

Patients with atopic dermatitis (AD) often suffer from mental health issues such as depression. Crosstalk between proinflammatory cytokines and hippocampal circuits may be a potent risk factor for behavioral abnormalities in depression, including anxiety, and mood disorders, which negatively controlled hippocampal neurogenesis via the upregulation of several proinflammatory cytokines. However, the mechanisms by which AD notably contribute to the development of depression are poorly understood. We found that increased IL-6 and soluble IL-6Rα (sIL-6Rα) in the peripheral blood specifically disrupted the blood-brain barrier and triggered depressive symptoms in NC/Tnd mice with spontaneous AD. The skin severity and depressive behavior correlated with markedly reduced numbers of doublecortin (DCX)-positive immature neurons in the hippocampus. Parabiotic pairs of mice with AD and unaffected mice showed disruption of hippocampal neurogenesis in the unaffected mice. Injection of neutralizing mAb against IL-6 significantly improved depressive behavioral signs and hippocampal neurogenesis. Furthermore, house dust mite-induced dermatitis gave rise to no depressive phenotypes in IL-6-deficient mice. Single-cell RNA sequencing analysis showed high expression of IL-6Rβ, unlike IL-6Rα, in hippocampal cells isolated from NC/Tnd mice. Addition of IL-6 and sIL-6Rα to neuronal progenitor cells cultured from the murine hippocampal dentate gyrus significantly reduced the number of DCX-positive cells, whereas IL-6 alone had no effect. Overall, these findings suggest that increased peripheral blood IL-6 and sIL-6Rα following atopic inflammation inhibits hippocampal immature neurogenesis via IL-6Rβ and is a critical risk factor for the development of mood and behavioral disorders in AD.

Jeju National University
Chonnam National University
University of Manchester
Tokyo University of Agriculture and Technology
Medizinische Universität Wien - AKH
Universität Wien
University of Tsukuba