Circulating IL-17 a as a downstream inflammatory indicator of depression: Insights from mendelian randomization and animal experiments.

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.