ATP-mediated Events in Peritubular Cells Contribute to Sterile Testicular Inflammation

Abstract

Peritubular myoid cells, which form the walls of seminiferous tubules in the testis, are functionally unexplored. While they transport sperm and contribute to the spermatogonial stem cell niche, specifically their emerging role in the immune surveillance of the testis and in male infertility remains to be studied. Recently, cytokine production and activation of Toll-like receptors (TLRs) were uncovered in cultured peritubular cells. We now show that human peritubular cells express purinergic receptors P2RX4 and P2RX7, which are functionally linked to TLRs, with P2RX4 being the prevalent ATP-gated ion channel. Subsequent ATP treatment of cultured peritubular cells resulted in up-regulated (pro-)inflammatory cytokine expression and secretion, while characteristic peritubular proteins, that is smooth muscle cell markers and extracellular matrix molecules, decreased. These findings indicate that extracellular ATP may act as danger molecule on peritubular cells, able to promote inflammatory responses in the testicular environment.

Ca2+ Signaling and IL-8 Secretion in Human Testicular Peritubular Cells Involve the Cation Channel TRPV2

“…Peritubular cells are smooth muscle-like cells and are thought to be pivotal for the transport of immotile sperm. Recent results obtained in HTPCs showed that they also contribute to the spermatogonial stem cell niche [ 6 , 29 ] and that they have immunological properties [ 11 , 12 ]. Peritubular cells possess androgen receptors, yet expression levels of TRPV2 in these cells was not affected by DHT, a potent androgen, added to the culture medium for up to 7days.…”

“…It was shown that activation of TRPV2 led to elevated levels of IL-6 and IL-8 in human periodontal ligament cells, and that deficiency of TRPV2 resulted in reduced macrophage infiltration and impaired phagocytosis [ 23 ]. As HTPCs are sources for cytokines [ 11 , 12 ], we explored consequences of TRPV2 activation. Despite expected heterogeneity between the samples stemming from individual patients [ 11 , 36 ], a proinflammatory influence of CBD became apparent with robustly increased levels of IL-8 in different experimental approaches.…”

“…In contrast, a role of IL-8 in normal testicular function remains to be determined [ 44 ] as testicular expression of the corresponding receptors for IL-8, CXCRs, was reported to be low or even absent. Yet, in cases of male infertility, which is associated with signs of sterile inflammation, it seems possible that IL-8 may have a say [ 11 , 12 , 45 , 46 ]. IL-8 is also involved in regulation of angiogenesis [ 47 , 48 ] with proangiogenic properties such as promoting proliferation, migration and tube-forming ability shown for human umbilical vein endothelial cells [ 49 ] and human aortic endothelial cells [ 50 ].…”

“…For instance, they are involved in paracrine signaling in the male gonad [ 5 ] and their participation in regulation of spermatogonial stem cells was shown for mice and men [ 6 , 7 , 8 ]. In addition, it became clear that in the human, peritubular cells can produce proinflammatory factors, express Toll-like receptors and have a say in the immune surveillance of the testis [ 9 , 10 , 11 , 12 ]. They may thus be players in sterile inflammation and male infertility [ 11 , 12 ].…”

“…In addition, it became clear that in the human, peritubular cells can produce proinflammatory factors, express Toll-like receptors and have a say in the immune surveillance of the testis [ 9 , 10 , 11 , 12 ]. They may thus be players in sterile inflammation and male infertility [ 11 , 12 ].…”