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

Lena Walenta,Frank-Michael Köhn,Jennifer Spehr,David Fleck,Hendrik Von Eysmondt,Marc Spehr,J Ullrich Schwarzer,Georg J Arnold,Thomas Fröhlich,Artur Mayerhofer

doi:10.1038/s41598-018-19624-3

Lena Walenta, Frank-Michael Köhn + Show 8 more

Open Access

https://doi.org/10.1038/s41598-018-19624-3

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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.

Highlights

Peritubular myoid cells are smooth muscle-like cells known for their contractile abilities that are of utmost importance for sperm transport[7,8]
Expression of purinoceptor subtypes P2RX4 and P2RX7 in cultured human testicular peritubular cells (HTPCs) of different patients was demonstrated on both, transcript and protein level (Fig. 1a,b)
Basal P2RX4 and P2RX7 receptor mRNA expression levels, and ACTA2 expression levels varied between cultured cells from individual patients (Fig. 1c)

Summary

Introduction

Peritubular myoid cells are smooth muscle-like cells known for their contractile abilities that are of utmost importance for sperm transport[7,8]. Previous studies, including proteomic and secretomic analyses, revealed that these human testicular peritubular cells (HTPCs) secrete ECM components and act as paracrine signalling cells[9]. They secrete immunoregulatory factors[10]. Biglycan-induced TLR signalling triggered an immune response including pro-inflammatory cytokine production and secretion[13,14] In this context, simultaneous activation of TLR2/4 and the purinergic receptor isoforms P2RX4 and P2RX7 by biglycan has been discovered[15]. Potential origins of extracellular ATP are infiltrating immune cells like mast cells and macrophages, as well as Sertoli cells[17,18] Both cell types reside in the immediate vicinity of peritubular cells[3,19,20].

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