Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.innate immunity | sterile inflammation | allergy | Mincle | cholesterol sulfate

Sertoli cells (SCs) are supporting cells in the mammalian testis that proliferate throughout fetal and postnatal development but exit the cell cycle and differentiate at puberty. In our previous study, we isolated a population of highly proliferative Sertoli-like cells (SLCs) from the region of the adult mouse testis containing the rete testis and adjacent seminiferous tubules. Here RNA-seq of the adult SLC culture as well as qPCR analysis and immunofluorescence of the adult and immature (6 dpp) SLC cultures were performed that allowed us to identify SLC-specific genes, including Pax8, Cdh1, and Krt8. Using these, we found that SLCs are mostly localized in the rete testis epithelium; however, some contribution of transitional zones of seminiferous tubules could not be excluded. The main feature of SLCs indicating their relationship to SCs is DMRT1 expression. More than 40% of both adult and immature SLCs expressed DMRT1 at different levels in culture. Only rare DMRT1+ cells were detected in the adult rete testis, whereas more than 40% of cells were positively stained for DMRT1 in the immature rete testis. One more SC protein, AMH, was found in some rete cells of the immature testis. It was also demonstrated that SLCs expressed such SC genes as Nr5a1, Dhh, Gdnf, and Kitl and interacted with germ cells in 3D co-culture with immature testicular cells. All these similarities between SLCs and rete cells on one the hand and SCs on the other, suggest that rete cells could share a common origin with SCs.

Background: The rete testis connects seminiferous tubules of the testis with efferent ducts having a mesonephric origin. The development of the rete testis is insufficiently studied, but there is evidence suggesting that it originates from gonadal cells. Here, the formation of the rete testis was investigated from E11.5 to E16.5 using immunofluorescent staining and 3D-modeling. Results: The rete testis became visible by SOX9 and PAX8 staining starting from E12.5. It was located in the mesonephros but connected with testis cords formed by Sertoli cells expressing SOX9, AMH, DMRT1. Between E13.5 and E14.5, AMH+ network of testis cords at the mesonephric side began to disintegrate in a gradient-dependent manner along the anterior-posterior axis of the gonad and connections between testis cords gradually lost AMH becoming a part of the rete. Cells combining features of Sertoli and rete cells (PAX8+ AMH+ and DMRT1+ AMH− cells) were detected starting from E14.5, suggesting that some rete cells originated from Sertoli cells. The rete ovarii, a female counterpart of the rete testis, developed in a similar way as the rete testis until E13.5. Conclusions: A part of the rete testis originates from connections between testis cords. Evidence that Sertoli cells contribute to rete cells is provided.

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SUMMARYAcute and chronic infections of the seminal tract are among the most common causes of male infertility. As at least half of male infertility cases are classified as idiopathic, some of these cases might be attributed to asymptomatic infection. The detection and quantification of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpes virus type 6 (HHV-6) DNA in semen samples were performed. A total of 232 patients were divided into five groups: (i) infertile men with varicocoele; (ii) men with idiopathic infertility; (iii) infertile men with chronic inflammatory urogenital tract diseases (IUTD); (iv) fertile men with IUTD and (v) men whose partners had a history of pregnancy loss. In the study population, the prevalence of viral DNA was 17.7, 3.4% for EBV, 5.2% for CMV, 6.5% for HHV-6, 0.43% for EBV + CMV, 0.87% for EBV + HHV-6 and 1.3% for CMV + HHV-6. The median viral loads for EBV, CMV and HHV-6 were 500, 2250 and 250 copies/mL respectively. Of the sperm cell fractions, derived from infected samples 87.5% contained viral DNA. No association between EBV and fertility disorders or IUTD was found. CMV detection was much higher in the group of patients with infertility and concomitant IUTD compared with the other groups combined (18.5% vs. 5.4%, p = 0.03) and associated with reduced sperm cell count (39.5 9 10 6 /mL vs. 72.5 9 10 6 /mL, p = 0.036). Immunostaining of spermatozoa from infected samples and in vitro-infected cells detected CMV in sperm heads, tails and connecting pieces and revealed attachment to sperm membrane and intracellular localization. HHV-6 was the more common in fertile men with chronic IUTD than in the other groups combined (19% vs. 6.3%, p = 0.018) and had no effect on sperm parameters. The results suggest that both CMV and HHV-6 may contribute to the aetiology of IUTD and, moreover, CMV-associated IUTD can lead to male sterility.