Alternative polarization of resident macrophages improves hyperglycemia-associated male infertility

Recent studies have demonstrated that hyperglycemia induces inflammation in male reproductive system to cause sperm damages and infertility, which may be associated with re-polarization of tissue macrophages from an anti-inflammation M2-like subtype to a pro-inflammation M1-like subtype. However, the underlying mechanisms are not fully determined and a practical approach to interfere with the progression of infertility is lacking. Here, we transduced the testicular macrophages back to the M2-like phenotype with adeno-associated viruses carrying an M2-trigger, Jumonji domain-containing protein D3 (JMJD3), under a macrophage-specific CD68 promoter (CD68p-JMJD3), in streptozotocin-induced diabetic mice. We found that JMJD3-induced M2-polarization of testicular macrophages significantly improved the mating capability of diabetic male mice. The diabetes-induced impairment of the motility of spermatozoa and the decreases in the serum and testicular testosterone levels were both significantly alleviated in CD68p-JMJD3-treated diabetic mice. Thus, our study proposes a practical strategy to treat hyperglycemia-associated infertility.