Pathological mechanism of non-obstractive oligo-/azo-ospermia (NOA), one of male infertilities in which haploid spermatozoa are reduced or absent, remains to be elucidated. Although recent study reported that the expression of interleukin-1 receptor antagonist (Il1rn) is reduced in the testes of NOA patients, Il1rn deficient (ΔRA) male mice are fertile. However, we found that simultaneous loss of Il1rn and Il1r2 (coding decoy receptor for IL1) results in male infertility, suggesting that dysregulation of IL1 activity is an etiology candidate of NOA. From these contexts, we aimed to elucidate how IL1 dysregulation cause NOA-like symptoms in mice.
We found that mice deficient for Il1rn and Il1r2 (ΔRAΔR2 mice) exhibit male infertility that are accompanied with testicular regression. Testes of sexually maturated 8-weeks-old ΔRAΔR2 mice showed reduction of elongated spermatids, exogenous localization of round spermatids in epididymis, and Leydig cell atrophy. These data suggested that spermatogenic defects are caused by decreased testosterone concentration due to Leydig cell atrophy. Considering that inflammatory responses such as immune cell infiltration or cytokine induction (TNF, Il6, Il17a1) were not observed, it is likely that male infertility of ΔRAΔR2 mice is attributed to dysfunction of hypothalamic-pituitary axis to produce luteinizing hormone (LH). Leydig cell atrophy in mutant mice deficient for LH signaling also supports this possibility. From these observation, we hypothesized that male infertility in ΔRAΔR2 mice is caused by dysfunction of hypothalamic-pituitary axis induced by dysregulation of IL1 signaling. In addition to the validation of our hypothesis, it is also intriguing to unveil the cytokine network inducing IL1-dependent NOA-like phenotype in mice.