Cytokine · 2026
Circulating IL-17 a as a downstream inflammatory indicator of depression: Insights from mendelian randomization and animal experiments.
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Lu Zhenchen, Yang Qiaoyu, Hu Shansong, Wu Han, Lu Liuliu, Shao Yiwei, Ye Bingqing, Li Li, Li Zeng, Li Rong, Liu Zhicheng
Аннотация
BACKGROUND: Previous studies have established a strong link between central nervous system inflammation and depression development. However, the role and function of circulating cytokines in depression remain a topic of debate.
METHODS: Bidirectional MR analyses used GWAS data from the GWAS Catalog, UK Biobank, and IEU database, including two depression cohorts and 41 circulating cytokines. Animal experiments explored the association between IL-17 A, IL-1β, and depression by assessing cytokine expression in control and CUMS rats, with or without IL-17 A/IL-1β inhibitors.
RESULTS: A potential directional association was found between depression and increased circulating IL-17 A (OR: 7.896, 95%CI: 1.962-31.782, P = 0.004, FDR = 0.019), with consistent findings in an independent cohort (OR: 1.732, 95%CI: 1.012-2.963, P = 0.045, FDR = 0.049). Circulating IL-1β was suggested as a risk factor for depression in both cohorts (OR: 1.036, 95%CI: 1.0002-1.0727, P = 0.049, FDR = 0.049; OR = 1.015, 95%CI: 1.002-1.029, P = 0.028, FDR = 0.046). Another MR study suggested IL-17 A exacerbated IL-1β dysregulation in depression (OR: 1.142, 95%CI: 1.034-1.261, P = 0.009, FDR = 0.031; OR: 1.224, 95%CI: 1.093-1.371, P < 0.001, FDR < 0.001). Animal experiments showed dynamic elevations of IL-17 A and IL-1β under CUMS. IL-1β inhibition alleviated depressive-like symptoms, whereas IL-17 A inhibition had little effect.
CONCLUSION: Our findings suggest that circulating IL-17 A may serve as a potential downstream inflammatory indicator, but not a causative factor for depression. A mutually reinforcing relationship may exist between elevated IL-1β and IL-17 A and depression.
METHODS: Bidirectional MR analyses used GWAS data from the GWAS Catalog, UK Biobank, and IEU database, including two depression cohorts and 41 circulating cytokines. Animal experiments explored the association between IL-17 A, IL-1β, and depression by assessing cytokine expression in control and CUMS rats, with or without IL-17 A/IL-1β inhibitors.
RESULTS: A potential directional association was found between depression and increased circulating IL-17 A (OR: 7.896, 95%CI: 1.962-31.782, P = 0.004, FDR = 0.019), with consistent findings in an independent cohort (OR: 1.732, 95%CI: 1.012-2.963, P = 0.045, FDR = 0.049). Circulating IL-1β was suggested as a risk factor for depression in both cohorts (OR: 1.036, 95%CI: 1.0002-1.0727, P = 0.049, FDR = 0.049; OR = 1.015, 95%CI: 1.002-1.029, P = 0.028, FDR = 0.046). Another MR study suggested IL-17 A exacerbated IL-1β dysregulation in depression (OR: 1.142, 95%CI: 1.034-1.261, P = 0.009, FDR = 0.031; OR: 1.224, 95%CI: 1.093-1.371, P < 0.001, FDR < 0.001). Animal experiments showed dynamic elevations of IL-17 A and IL-1β under CUMS. IL-1β inhibition alleviated depressive-like symptoms, whereas IL-17 A inhibition had little effect.
CONCLUSION: Our findings suggest that circulating IL-17 A may serve as a potential downstream inflammatory indicator, but not a causative factor for depression. A mutually reinforcing relationship may exist between elevated IL-1β and IL-17 A and depression.