MyD88 Signaling in Sertoli Cells Mediates LPS-Induced Orchitis in Mice.

Abstract

Orchitis, a prevalent male reproductive disorder that can severely impair fertility and potentially result in infertility. Sertoli cells orchestrate testicular immune responses during orchitis by modulating local inflammation and maintaining blood-testis barrier integrity. While Myeloid differentiation primary response protein 88 (MyD88), a critical adaptor molecule in the TLR4 signaling pathway, is known to mediate immune responses, its cell-specific role in Sertoli cells during lipopolysaccharide (LPS)-induced orchitis remains elusive. Using an murine orchitis model established through intraperitoneal LPS administration, we observed pronounced testicular inflammation concurrent with dramatic upregulation of MyD88 protein levels (P < 0.05). To further investigate the Sertoli cell-specific function of MyD88, we generated conditional Myd88 knockout (cKO) mice. Compared to controls, cKO mice showed marked attenuation of testicular edema along with improved sperm motility and viability post-LPS challenge. Myd88 deletion also suppressed LPS-triggered surges in pro-inflammatory cytokines (TNF-α, IL-6), maintained seminiferous tubule architecture, and mitigated neutrophil infiltration. Further studies demonstrated that Myd88 deletion rescued LPS-induced BTB disruption by restoring the expression of key BTB components (Connexin43, Claudin-11). Additionally, NF-κB signaling pathway is activated by MyD88 mediated inflammatory responses. Collectively, these findings uncover Sertoli cell specific MyD88 as a key regulator in LPS-induced orchitis pathogenesis, highlighting its potential as a promising therapeutic target for orchitis.