Testosterone upregulates progesterone production in mouse testicular interstitial macrophages, whose niche likely provides properties of progesterone production to tissue-resident macrophages.

The niche of the macrophages (Mø) residence concept is now accepted; Mø colonize tissue/organ-specific microenvironments (niches) that shape Mø to perform tissue/organ-specific functions. Recently, we developed a simple propagation method for tissue-resident Mø by mixed culture with the respective tissue/organ-residing cells acting as the niche and demonstrated that testicular interstitial Mø propagated by mixed culture with testicular interstitial cells showing properties of Leydig cells in culture (we termed them "testicular Mø niche cells") produce progesterone (P4) de novo. Based on previous evidence of testosterone production downregulation in Leydig cells by P4 and androgen receptor expression in testicular Mø, we proposed a local feedback loop of testosterone production between Leydig cells and testicular interstitial Mø. To verify this hypothesis, we further examined P4 de novo production in propagated testicular interstitial Mø treated with testosterone using ELISA and found that exogenous testosterone upregulates P4 production in testicular interstitial Mø. Thus, testosterone production, which is controlled by the local feedback loop, likely becomes more reliable. Moreover, we examined whether tissue-resident Mø other than testicular interstitial Mø can be transformed into P4-producing cells by mixed culture with testicular Mø niche cells: using RT-PCR and ELISA we found that splenic Mø newly acquired P4 production properties by mixed-culturing with testicular Mø niche cells for 7 days. This likely indicates the substantiative in vitro evidence on the niche concept and possibly opens the door to using P4-secreting Mø as a transplantation tool for clinical application due to the migratory property of Mø into inflammatory sites.