TNIP2 mediates GRβ-promoted inflammation and is associated with severity of major depressive disorder

In depression, continual activation of the hypothalamic-pituitaryadrenal (HPA) axis with excess cortisol release leads to impair sensitivity of the glucocorticoid receptor (GR) and increase activity of the pro-inflammatory immune responses. Aberrant expression of GR has been associated with inflammation in patients with major depressive disorder (MDD). Our previous studies showed that the aberrant expression of TNFAIP3 gene, which encodes the NF-κB regulatory protein A20, TNFAIP3-associated proteins and Toll-like receptors (TLRs) are involved in inflammation-associated depression. However, the link between desensitization of GR actions and negative regulation of the TLRs-mediated inflammatory pathway in MDD is yet to be established. Here, we examined the association of depression severity, measured via the 17-item Hamilton Depression Rating Scale (HAMD-17), with the mRNA expression profiling of GRα, GRβ, TNFAIP3-interacting proteins (TNIP), including TNIP1, TNIP2, and TNIP3, and TNFAIP3-like proteins, such as cezanne1, cezanne2, trabid, and valosin-containing protein p97/p47 complex-interacting protein p135 (VCIP135), in monocytes from 69 patients with MDD and 42 healthy controls. Herein we found the mRNA expressions of GRβ and TNIP2 were significantly higher in monocytes from patients with MDD. Notably, TNIP2 level was positively correlated with the GRβ expression and severity of depression, as determined via Pearson's correlation analysis. Mechanistically, we demonstrated that overexpression of GRβ promotes the mRNA levels of TNIP2 and tumor necrosis factor alpha (TNF-α) in human monocytes. The promoting effect of GRβ on TNF-α expression was partially attenuated upon depletion of TNIP2, suggesting that TNIP2 was required for GRβ-mediated enhancement of TNF-α levels. Together, these results suggest that activation of GRβ/TNIP2/TNF-α axis may induce inflammation in MDD patients and targeting this newly identified pathway may help in the development of better therapeutic approaches to reduce the development of MDD.