Elevated IL-22 as a result of stress-induced gut leakage suppresses septal neuron activation to ameliorate anxiety-like behavior
Mengyu Xia, Junmei Lü, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Yi Han, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu
Abstract
Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress. • Stress induces elevated IL-22 following gut leakage and microbiota exposure • Intestinal T H 17 cells expand during stress, which contributes to elevated systemic IL-22 • IL-22 suppresses septal neuron activation and prevents stress-elicited anxiety • Exogenous IL-22 injection mitigates stress-related anxiety and depression disorders Immune activation is often thought to exacerbate stress-related mental disorders. Here, Xia, Lu, Lan, et al. reveal elevated IL-22 derived from the gut during the early phase of repeated stress. IL-22 suppresses neuron activation in the brain and mitigates stress-induced anxiety, suggesting an immune defense mechanism against psychological insults.