IL-22 Functions Through the "Gut-Brain Axis" to Mitigate Psychological Stress: New Findings from Dr. Xiaofei Yu's lab
Source：Xiaofei Yu
2025-01-21
Psychological stress represents a significant risk factor for mental disorders. The body's response to psychological stress involves complex coordination between the nervous system and peripheral organs, with dysregulation often resulting in mental illness. Although the stress-induced immune response is well-documented and typically viewed as a pathological burden that exacerbates stress-related disorders, its potential adaptive benefits have remained poorly understood.
On January 14, 2025, a study entitled "Stress-induced gut leakage elevates IL-22 levels which suppress septal neuron activation to ameliorate anxiety-like behavior", led by Dr. Xiaofei Yu from the School of Life Sciences at Fudan University, was published in Immunity. This study demonstrates that during the early phase of stress-induced immune activation, IL-22 produced by gut TH17 cells mitigates anxiety-like behavior in mice. This effect occurs through direct suppression of neuronal activation in the septal region of the brain, revealing IL-22's critical role in bridging the "gut-brain axis" during psychological stress.
Key Findings
1. Stress-Induced Gut Leakage and IL-22 Activation
Through a mild restraining stress model, the team observed early immune activation characterized by gut leakage, which promoted the IL1β-TH17-IL-22 pathway. Using IL-22-deficient mice, IL-22-supplementation, IL-22 elevated Tcrb deficient mice, and IL-22 depleted antibiotic-treated mice, they demonstrated that IL-22 significantly reduces anxiety-like behaviors upon stress induction. A second stress model confirmed these observations, recapitulating gut leakage, elevated IL-22 levels, and improved anxiety-related behavior. These results highlight the beneficial role of IL-22 in stress adaptation.
2. Mechanism of IL-22 Action in the Septum brain region
Using whole-brain neuronal activation mapping via iDISCO, the team identified a positive correlation between stress-induced anxiety and neuronal activation in the septum. Conversely, IL-22 levels negatively correlated with septal neuronal activation. They found that stress induced blood-brain barrier (BBB) disruption, allowing circulating IL-22 to enter the septum. Combining fluorescence in situ hybridization (FISH), single-nucleus RNA sequencing, and immunohistochemistry (IHC), the team validated IL-22 receptor expression on septal neurons. IL-22 suppresses septal neuronal activation through the JAK-STAT3 pathway. AAV-mediated gene deletion of IL-22 receptor in septal neurons confirmed that IL-22 directly modulates septal neuronal activation to alleviate stress-induced anxiety.
3. Clinical Relevance and Depression Models
Patients with major depressive disorder (MDD) showed significantly lower serum IL-22 levels compared to healthy controls . Moreover, patients with higher depression scores or comorbid anxiety exhibited even lower IL-22 levels. In a mouse model of depression, administration of exogenous IL-22 significantly improved depressive behaviors, suggesting potential therapeutic applications.
Implications and Scientific Impact
This study reveals an unexpected beneficial role of early immune activation during stress, demonstrating how IL-22 produced by gut TH17 cells crosses the compromised BBB to suppress septal neuronal activity, thereby reducing stress-induced anxiety-like behaviors. These findings provide new insights into the protective role of the immune system against psychological insults and suggest targeting the IL-22-mediated gut-brain axis as a potential intervention strategy for stress-related psychological diseases. This study has been previewed in Immunity and highlighted by Nature Reviews Immunology.
Research Team
Dr. Xiaofei Yu from Fudan University served as the senior corresponding author, with Dr. Anoj Ilanges and Dr. Xinyu Zhou as co-corresponding authors. The study's first authors include Mengyu Xia (PhD student, Fudan University), Dr. Junmei Lu (postdoctoral fellow, Fudan University), and Jiabin Lan (Master’s student, Fudan University). Dr. Boxun Lu (Fudan University) and Dr. Wei Shen (ShanghaiTech University) also provided critical assistance to this study.
Article Link: https://www.cell.com/immunity/fulltext/S1074-7613(24)00523-5
On January 14, 2025, a study entitled "Stress-induced gut leakage elevates IL-22 levels which suppress septal neuron activation to ameliorate anxiety-like behavior", led by Dr. Xiaofei Yu from the School of Life Sciences at Fudan University, was published in Immunity. This study demonstrates that during the early phase of stress-induced immune activation, IL-22 produced by gut TH17 cells mitigates anxiety-like behavior in mice. This effect occurs through direct suppression of neuronal activation in the septal region of the brain, revealing IL-22's critical role in bridging the "gut-brain axis" during psychological stress.
Key Findings
1. Stress-Induced Gut Leakage and IL-22 Activation
Through a mild restraining stress model, the team observed early immune activation characterized by gut leakage, which promoted the IL1β-TH17-IL-22 pathway. Using IL-22-deficient mice, IL-22-supplementation, IL-22 elevated Tcrb deficient mice, and IL-22 depleted antibiotic-treated mice, they demonstrated that IL-22 significantly reduces anxiety-like behaviors upon stress induction. A second stress model confirmed these observations, recapitulating gut leakage, elevated IL-22 levels, and improved anxiety-related behavior. These results highlight the beneficial role of IL-22 in stress adaptation.
2. Mechanism of IL-22 Action in the Septum brain region
Using whole-brain neuronal activation mapping via iDISCO, the team identified a positive correlation between stress-induced anxiety and neuronal activation in the septum. Conversely, IL-22 levels negatively correlated with septal neuronal activation. They found that stress induced blood-brain barrier (BBB) disruption, allowing circulating IL-22 to enter the septum. Combining fluorescence in situ hybridization (FISH), single-nucleus RNA sequencing, and immunohistochemistry (IHC), the team validated IL-22 receptor expression on septal neurons. IL-22 suppresses septal neuronal activation through the JAK-STAT3 pathway. AAV-mediated gene deletion of IL-22 receptor in septal neurons confirmed that IL-22 directly modulates septal neuronal activation to alleviate stress-induced anxiety.
3. Clinical Relevance and Depression Models
Patients with major depressive disorder (MDD) showed significantly lower serum IL-22 levels compared to healthy controls . Moreover, patients with higher depression scores or comorbid anxiety exhibited even lower IL-22 levels. In a mouse model of depression, administration of exogenous IL-22 significantly improved depressive behaviors, suggesting potential therapeutic applications.
Implications and Scientific Impact
This study reveals an unexpected beneficial role of early immune activation during stress, demonstrating how IL-22 produced by gut TH17 cells crosses the compromised BBB to suppress septal neuronal activity, thereby reducing stress-induced anxiety-like behaviors. These findings provide new insights into the protective role of the immune system against psychological insults and suggest targeting the IL-22-mediated gut-brain axis as a potential intervention strategy for stress-related psychological diseases. This study has been previewed in Immunity and highlighted by Nature Reviews Immunology.
Research Team
Dr. Xiaofei Yu from Fudan University served as the senior corresponding author, with Dr. Anoj Ilanges and Dr. Xinyu Zhou as co-corresponding authors. The study's first authors include Mengyu Xia (PhD student, Fudan University), Dr. Junmei Lu (postdoctoral fellow, Fudan University), and Jiabin Lan (Master’s student, Fudan University). Dr. Boxun Lu (Fudan University) and Dr. Wei Shen (ShanghaiTech University) also provided critical assistance to this study.
Article Link: https://www.cell.com/immunity/fulltext/S1074-7613(24)00523-5
