MKP1 preserves testicular immune privilege and supports spermiogenesis by suppressing IKKβ/NF-κB/IL-6 signaling in Sertoli cells

MAPK phosphatase 1 (MKP1) in Sertoli cells has been shown to protect the blood-testis barrier during LPS-induced inflammation, but its role under physiological conditions is unclear. Here, we show that MKP1 knockout mice exhibit subfertility, reduced sperm counts, increased sperm abnormalities, and impaired spermiogenesis. MKP1 deficiency compromises blood-testis barrier integrity, elevates testicular IL-6 expression, and increases serum anti-sperm antibodies. Mechanistically, MKP1 interacts with IKKβ in Sertoli cells to suppress IKKβ/NF-κB signaling and downstream IL-6 expression. Notably, IL-6 inhibition with LMT-28 rescues the spermatogenic defects in MKP1-deficient mice. Collectively, this study establishes that MKP1 in Sertoli cells maintains testicular immune privilege via the IKKβ/NF-κB/IL-6 axis to support spermiogenesis, offering a potential therapeutic target for inflammatory spermatogenic disorders.