The discovery that submicron-sized extracellular vesicles (EVs) are generated by both prokaryotic and eukaryotic cells might have a profound effect on experimental and clinical sciences, and could pave the way for new strategies to combat various diseases. EVs are carriers of pathogen-associated and damage-associated molecular patterns, cytokines, autoantigens and tissue-degrading enzymes. In addition to a possible role in the pathogenesis of a number of inflammatory conditions, such as infections and autoimmune diseases, EVs, including microvesicles (also known as microparticles), exosomes and apoptotic vesicles, have therapeutic potential and might be used as biomarkers for inflammatory diseases. Therefore, molecular diagnostics and targeted therapy could benefit from expanding knowledge in the field. In this Review, we summarize important developments and propose that extracellular vesicles could be used as therapeutic vehicles and as targets for the treatment and prevention of inflammatory diseases.

Emerging role of extracellular vesicles in inflammatory diseases

Semen contains relatively ill-defined regulatory components that likely aid fertilization, but which could also interfere with defense against infection. Each ejaculate contains trillions of exosomes, membrane-enclosed subcellular microvesicles, which have immunosuppressive effects on cells important in the genital mucosa. Exosomes in general are believed to mediate inter-cellular communication, possibly by transferring small RNA molecules. We found that seminal exosome (SE) preparations contain a substantial amount of RNA from 20 to 100 nucleotides (nts) in length. We sequenced 20–40 and 40–100 nt fractions of SE RNA separately from six semen donors. We found various classes of small non-coding RNA, including microRNA (21.7% of the RNA in the 20–40 nt fraction) as well as abundant Y RNAs and tRNAs present in both fractions. Specific RNAs were consistently present in all donors. For example, 10 (of ∼2600 known) microRNAs constituted over 40% of mature microRNA in SE. Additionally, tRNA fragments were strongly enriched for 5’-ends of 18–19 or 30–34 nts in length; such tRNA fragments repress translation. Thus, SE could potentially deliver regulatory signals to the recipient mucosa via transfer of small RNA molecules.

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Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions

The seminal fluid is a complex medium containing a great variety of molecules, mainly produced by sex accessory glands, and also cells other than spermatozoa (e.g. leucocytes). In this paper, I review current knowledge on composition of seminal fluid in both vertebrates (mainly mammals) and invertebrates (mainly insects) with internal fertilisation, in the light of possible benefits of seminal fluid components to males (e.g. sperm capacitation, sperm competition and fertilisation), possible costs to males (e.g. autoimmunity, antigenic effects), potential benefits to females being inseminated (e.g. food, immunostimulation and antibiotic effects) and potential costs to females (e.g. transmission of venereal diseases). The diversity of microorganismal, cellular and molecular components of seminal fluids can be interpreted in the light of emergence of co-adapted complexes, host–parasite coevolution, male–female arms races, sperm competition, pleiotropy and redundancy of function.

Complexity of seminal fluid: a review

Background: Shedding microvesicles are membrane released vesicles derived directly from the plasma membrane. Exosomes are released membrane vesicles of late endosomal origin that share structural a ...

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Cardiomyocyte Microvesicles Contain DNA/RNA and Convey Biological Messages to Target Cells

A sperm-driven micromotor is presented as a targeted drug delivery system, which is appealing to potentially treat diseases in the female reproductive tract. This system is demonstrated to be an efficient drug delivery vehicle by first loading a motile sperm cell with an anticancer drug (doxorubicin hydrochloride), guiding it magnetically, to an in vitro cultured tumor spheroid, and finally freeing the sperm cell to deliver the drug locally. The sperm release mechanism is designed to liberate the sperm when the biohybrid micromotor hits the tumor walls, allowing it to swim into the tumor and deliver the drug through the sperm–cancer cell membrane fusion. In our experiments, the sperm cells exhibited a high drug encapsulation capability and drug carrying stability, conveniently minimizing  toxic side effects and unwanted drug accumulation in healthy tissues. Overall, sperm cells are excellent candidates to operate in physiological environments, as they neither express pathogenic proteins nor proliferate to...

Sperm-Hybrid Micromotor for Targeted Drug Delivery

Numerous reports have ascribed immunosuppressive activity to human seminal plasma and there is growing agreement that much of this activity can be accounted for by the very high levels of E series prostaglandins present (up to 300 microM 19-hydroxy prostaglandin E). However not all suppressive activity is due to prostaglandin since several reports have appeared of high molecular weight active substances and we have found that stripped seminal plasma is still effective in inhibiting the mitogen-induced proliferation of lymphocytes. In this study such immunosuppressive activity has been separated by molecular size fractionation and the activity has been found to be particulate and corresponded to the previously reported prostasomes. These are trilaminar to multilaminar vesicles (150 nm diameter) which are secreted by the prostate. Pure preparations of prostasomes inhibited mitogen-induced lymphoproliferation in a dose-dependent manner with a concentration of prostasomes equivalent to 40% of that seen in seminal fluid giving 69% suppression of thymidine incorporation. The suppressive activity survived boiling and therefore was unlikely to be due to enzymatic action associated with these organelles. Interaction with the accessory cells, involved in full development of the lymphoproliferation induced by mitogen, was indicated and this possibility was supported by the demonstration of a direct effect of prostasomes on macrophage function using a mouse macrophage cell line. The prostasomes in semen may play a complementary role to the prostaglandins in neutralizing the immune defences of the female reproductive tract. This combination would allow the alloantigenic spermatozoa the best chance of achieving fertilization, but at the same time leave the recipient open to any infection present in the semen.

Extracellular organelles (prostasomes) are immunosuppressive components of human semen.

In this paper we report studies undertaken to determine the contribution of seminal prostaglandins to some of the known immunosuppressive properties of human seminal plasma. Initial studies revealed that fractions of seminal plasma enriched in E series prostaglandins, obtained by reverse phase chromatography, had a pronounced inhibitory effect on the PHA-induced proliferation of peripheral blood lymphocytes and on the NK-cell-mediated lysis of K562 target cells. Additional investigations revealed that similar inhibitory effects could be achieved with purified PGE2 (10(-6) to 10(-9) M) and 19-OH PGE1 (10(-6) to 10(-7) M), both of which are present in uniquely high concentrations in human seminal plasma. In contrast, 19-OH PGF1 which is found in lower concentrations in semen was slightly stimulatory in proliferative assays and had no effect on NK-cell-mediated cytotoxicity. Removal of the seminal prostaglandins by absorption chromatography resulted in a dramatic decrease in immune suppressive activity. Further studies with fractions obtained by ion-exchange HPLC of desalted seminal plasma indicated that prostaglandins complexed with seminal proteins, and these too were immunosuppressive. The possible relevance of these results to sexually transmitted disease is discussed.

Immunosuppression by seminal prostaglandins.

Human seminal plasma has uniquely high concentrations of PGE and 19-hydroxy PGE but the function of these PGs has not been elucidated. PGs of the E series have been shown to be paracrine and autocrine regulators of the function of immune cells and high levels of PGE have been shown consistently to suppress function in such cells. Human seminal plasma has a potent immunosuppressive effect and evidence is accumulating that this is largely due to PG components. In this study the effects of human seminal plasma on the killing activity of natural killer (NK) cells as judged by 51Cr release from K562 cells have been studied in groups of fertile and infertile men. Although there was no significant difference in the PGE, 19-hydroxy PGE or the NK cell inhibitory activity in the two groups, the inhibition of NK cell activity was closely correlated with the PGE and the 19-OH PGE content of the seminal plasma in the fertile group. This finding is further evidence that the major contribution to the immunosuppressive properties of human semen is provide by the high concentration of PGs of the E series in this fluid.

Immunosuppression by seminal plasma from fertile and infertile men: inhibition of natural killer cell function correlates with seminal PG concentration.

T.B. Hargreave

Papers

Extracellular organelles (prostasomes) are immunosuppressive components of human semen.

Immunosuppression by seminal prostaglandins.

Immunosuppression by seminal plasma from fertile and infertile men: inhibition of natural killer cell function correlates with seminal PG concentration.