Despite the prevailing view that immune activation exacerbates stress-related psychological conditions, Mengyu Xia et al. speculated that stress-induced immune activation may have some benefits given its evolutionary conservation. Reporting in Immunity, they now show that stress-induced gut leakage and immune activation lead to the release of IL-22, which acts on septal neurons in the brain to dampen their activation and reduce concomitant anxiety behaviour.

To model mildly stressful conditions, mice were restrained for 30 minutes each day for 3 days. This was sufficient to increase gut permeability and cause immune activation, as indicated by activation of intestinal NF-κB and altered peripheral cytokine profiles. In particular, higher IL-22 levels were observed in stressed mice than in resting mice. Studies using reporter mice showed that the IL-22 increase was primarily derived from expanded populations of T helper 17 (TH17) cells. TH17 cell expansion was stimulated by microbiota-derived signals that drove an increase in circulating IL-1β. Accordingly, depletion of the microbiota with antibiotics prevented the stress-induced increase in IL-1β and IL-22-producing TH17 cells.