Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis.

Abstract

Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.

• Authors: Hong-Guang Zhang, Bin Wang, Yong Yang, Xuan Liu, Junjie Wang, Ning Xin, Shifeng Li, Ying Miao, Qiuyu Wu, Tingting Guo, Yukang Yuan, Yibo Zuo, Xiangjie Chen, Tengfei Ren, Chunsheng Dong, Jun Wang, Hang Ruan, Miao Sun, Xingshun Xu, Hui Zheng
• Journal: Cell research (Cell Res) Vol. 32 Issue 10 Pg. 897-913 (10 2022) ISSN: 1748-7838 [Electronic] England
• PMID: 35821088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Ahi1 protein, mouse
• Antiviral Agents
• Arginine Vasopressin
• Meptazinol
• Interferons

Topics

• Adaptor Proteins, Vesicular Transport
• Animals
• Antiviral Agents
• Arginine Vasopressin
• Depression (metabolism)
• Depressive Disorder, Major
• Immunity, Innate
• Interferons
• Leukocytes, Mononuclear
• Meptazinol
• Mice