Fetal Sex Modulates Hofbauer Cells’ Response to Diabetes in Human Placenta

<b>Background</b>: Hofbauer cells (HBCs) are fetal-origin macrophages in the placental villous stroma that contribute to immune tolerance at the feto-maternal interface. They predominantly display an M2 phenotype, characterized by CD206 expression. <b>Methods</b>: Using immunohistochemistry and morphometric analysis, we quantified HBCs, assessed CD206 intensity and morphology, and evaluated apoptotic body accumulation in placental villi. Comparisons were made among pregnancies complicated by type 1 diabetes mellitus (T1DM), gestational diabetes mellitus (GDM), and normoglycemic controls, as well as between male and female fetuses. <b>Results</b>: Significant effects of maternal diabetes and fetal sex on CD206 intensity were observed ([diagnosis: F = 2773.00, <i>p</i> < 0.0001; sex: F = 12.19, <i>p</i> = 0.0005]), with a strong interaction (F = 165.40, <i>p</i> < 0.0001). In controls, CD206 intensity was higher in female than male fetuses (<i>p</i> < 0.0001). Across groups, CD206 intensity decreased progressively from controls to GDM and T1DM, with a more pronounced reduction in females. Reduced CD206 was associated with elongation and irregular HBC morphology and increased IL-1β (r = -0.392, <i>p</i> = 0.003; r = -0.609, <i>p</i> < 0.0001) suggesting less tolerogenic phenotype. For apoptotic bodies, significant main effects of maternal diabetes and fetal sex were detected ([diagnosis: F = 97.16, <i>p</i> < 0.0001; sex: F = 15.88, <i>p</i> = 0.0001]). Accumulation increased progressively from controls to GDM and T1DM, with higher counts in males. <b>Conclusions:</b> Maternal diabetes is associated with reduced CD206 intensity, altered HBC morphology, and accumulation of apoptotic bodies in placental villi. Our results suggest greater HBC plasticity, potentially contributing to a tolerogenic placental environment in females.