Toll-like receptor 4 (TLR4) as a possible pathological mechanism in hyperglycemia-associated testicular dysfunction

Hyperglycemia is a chief factor in diabetes, a complex disease associated with reproductive disorders, mainly testicular dysfunction, which contributes to male infertility. Leydig cells are the predominant cell population in the testis interstitium and, when stimulated, they are capable of initiating immune responses playing crucial roles in the mechanisms related to testis' homeostasis. These cells express TLR4, an innate immune receptor, which is known to be modulated by hyperglycemia in other cell populations and tissue types. Still, whether TLR4 contributes to hyperglycemia-associated testicular dysfunction remains elusive. Activation of TLR4 in response to high glucose levels involves redox imbalance and stimulation of transcriptional factors, especially nuclear factor (NF)-κB, which could be a potential pathological mechanism compromising the testis integrity. Additionally, emerging evidence shows crosstalk between TLR4 and Nrf2, an anti-inflammatory mediator that was previously shown to be reduced in diabetic testis. Therefore, we hypothesize that hyperglycemia-mediated TLR4 activation in testicular cells, especially Leydig cells might be a crucial event triggering oxidative stress and inflammation, which in turn, drives testicular dysfunction.