Testosterone deficiency fuels male depression through AR regulation and NLRP3-mediated neuroinflammation

Low testosterone levels have been associated with male depression, making testosterone replacement therapy (TRT) a potential treatment option. However, its effectiveness varies, and the underlying mechanisms remain unclear. Neuroinflammation is a significant factor in the pathogenesis of depression, yet limited studies have explored the connection between low testosterone and neuroinflammation in this context. To investigate this further, we conducted randomized controlled trials and animal model studies. Blood samples from 26 patients showed lower serum testosterone alongside increased levels of IL-1β, IL-18, NLRP3, and P2 × 7 in males diagnosed with major depressive disorder (MDD). Using a testosterone deprivation (Td) animal model, we observed that Td induced depressive-like behaviors, which were associated with heightened expression of IL-1β and IL-18 in the hippocampus and signs of inflammatory activation. NLRP3 was identified as a critical player in these processes, characterized by elevated TLRs expression, NF-κB activation, and increased P2 × 7 expression. TRT mitigated Td-related symptoms by inhibiting NLRP3-mediated neuroinflammation, a finding validated in an LPS-induced inflammatory cell model. Further analysis indicated that low serum testosterone activated hippocampal inflammation via downregulation of androgen receptor (AR) expression. TRT reduced neuroinflammation by enhancing AR expression and suppressing NLRP3 activation, leading to an improvement in depressive symptoms. These findings suggest a link between serum testosterone levels and depression through AR regulation and NLRP3-mediated neuroinflammation, providing clinical support for the association between testosterone and MDD, and endorsing TRT as a viable therapeutic approach for testosterone-deficient male MDD patients.