Summary Psychological stress and its sequelae are a major public health problem. While the immune system has been implicated in the development of stress-related disorders, how the immune signals modulate neural responses to stress is poorly understood. Contrary to our expectations, we found that the immune cytokine Interleukin (IL)-22 is the key mediator of an immune-to-brain pathway that diminishes, rather than amplifies, stress-induced anxiety. We showed that stress induced T H 17 differentiation and IL-22 production in the intestine following barrier dysfunction and microbiota stimulation. IL-22 then directly signaled to septal neurons in the brain to mitigate anxiety-like behavior. Accordingly, mice treated with exogenous IL-22 showed resilience to chronic stress-induced anxiety disorders. Our study thus reveals a previously-unappreciated immune-to-brain axis that defends against psychological stress, suggesting a potential intervention strategy for stress-related mental diseases.

Microbiota-stimulated Interleukin-22 regulates brain neurons and protects against stress-induced anxiety