High Glucose Supplementation Aggravates Experimental Autoimmune Epididymo-orchitis via Localized Th17 Skewing in the...

Chronic epididymo-orchitis contributes significantly to male infertility through immune cell infiltration and pro-inflammatory cytokine elevation. High glucose intake promotes Th17 differentiation and autoimmunity, but its effects on autoimmune testicular inflammation remain unclear.

To determine whether chronic high glucose supplementation exacerbates experimental autoimmune epididymo-orchitis (EAEO), impairs spermatogenesis, and drives CD4⁺ T-cell dysregulation, particularly Th17 polarization, in the reproductive tract.

EAEO was induced in male C57BL/6 mice with or without chronic 10% glucose supplementation in drinking water. Sperm parameters, ROS levels, apoptosis, and histopathology were evaluated. CD4⁺ T-cell subsets (Th1, Th17, Treg, TNF-α⁺ effector memory) were quantified by flow cytometry in testis, epididymis, spleen, and testicular inguinal lymph nodes (iLN) at days 30, 60, and 90 post-immunizations.

High glucose intake accelerated EAEO progression, markedly worsening sperm concentration and motility, elevating sperm ROS, increasing germ cell apoptosis, and causing severe histopathological damage. In the reproductive tract, glucose induced an upward trend of CD4⁺ T cells and late-phase selective Th17 skewing (days 60-90), with significant IL-17A⁺CD4⁺ Teff increases and accompanying TNF-α⁺CD4⁺CD44⁺ Teff upregulation, while IFN-γ⁺ Th1 responses remained modest. These pro-inflammatory changes were strictly localized, with no significant Th17, Th1, Treg, or TNF-α alterations in spleen or iLN.

Chronic high glucose exacerbates EAEO by intensifying oxidative stress, apoptosis, and tissue injury while promoting a late-phase, tissue-restricted Th17-biased CD4⁺ T-cell response in the testis and epididymis. These findings reveal a metabolic-immune axis that may accelerate immune-mediated male subfertility via localized Th17 mechanisms.