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Testicular exosomes disturb the immunosuppressive phenotype of testicular macrophages mediated by miR-155-5p in uropathogenic Escherichia coli-induced orchitis.

ABSTRACT: Male reproductive infections are known to shape the immunological homeostasis of the testes, leading to male infertility. However, the specific pathogenesis of these changes remains poorly understood. Exosomes released in the inflammatory microenvironment are important in communication between the local microenvironment and recipient cells. Here, we aim to identify the immunomodulatory properties of inflammatory testes-derived exosomes (IT-exos) and explore their underlying mechanisms in orchitis. IT-exos were isolated using a uropathogenic Escherichia coli (UPEC)-induced orchitis model and confirmed that IT-exos promoted proinflammatory M1 activation with increasing expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in vitro. We further used small RNA sequencing to identify the differential miRNA profiles in exosomes and primary testicular macrophages (TMs) from normal and UPEC-infected testes, respectively, and identified that miR-155-5p was highly enriched in IT-exos and TMs from inflammatory testes. Further study of bone marrow derived macrophages (BMDMs) transfected with miR-155-5p mimic showed that macrophages polarized to proinflammatory phenotype. In addition, the mice that were administrated IT-exos showed remarkable activation of TM1-like macrophages; however, IT-exos with silencing miR-155-5p showed a decrease in proinflammatory responses. Overall, we demonstrate that miR-155-5p delivered by IT-exos plays an important role in the activation of TM1 in UPEC-induced orchitis. Our study provides a new perspective on the immunological mechanisms underlying inflammation-related male infertility.

SUBMITTER: Xu J

PROVIDER: S-EPMC10226493 | biostudies-literature | 2023 May-Jun

REPOSITORIES: biostudies-literature

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Testicular exosomes disturb the immunosuppressive phenotype of testicular macrophages mediated by miR-155-5p in uropathogenic <i>Escherichia coli</i>-induced orchitis.

Xu Jia J He Chao C Fang Yi-Wei YW Hu Zhi-Yong ZY Peng Mei-Lin ML Chen Yuan-Yao YY Su Yu-Fang YF Liu Chun-Yan CY Zhang Hui-Ping HP Zhao Kai K

Asian journal of andrology 20230501 3

Male reproductive infections are known to shape the immunological homeostasis of the testes, leading to male infertility. However, the specific pathogenesis of these changes remains poorly understood. Exosomes released in the inflammatory microenvironment are important in communication between the local microenvironment and recipient cells. Here, we aim to identify the immunomodulatory properties of inflammatory testes-derived exosomes (IT-exos) and explore their underlying mechanisms in orchiti ...[more]

PMID: 35915541

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Project description:BackgroundHypersensitivity pneumonitis (HP) is an inflammatory disorder affecting lung parenchyma and often evolves into fibrosis (fHP). The altered regulation of genes involved in the pathogenesis of the disease is not well comprehended, while the role of microRNAs in lung fibroblasts remains unexplored.MethodsWe used integrated bulk RNA-Seq and enrichment pathway bioinformatic analyses to identify differentially expressed (DE)-miRNAs and genes (DEGs) associated with HP lungs. In vitro, we evaluated the expression and potential role of miR-155-5p in the phenotype of fHP lung fibroblasts. Loss and gain assays were used to demonstrate the impact of miR-155-5p on fibroblast functions. In addition, mir-155-5p and its target TP53INP1 were analyzed after treatment with TGF-β, IL-4, and IL-17A.ResultsWe found around 50 DEGs shared by several databases that differentiate HP from control and IPF lungs, constituting a unique HP lung transcriptional signature. Additionally, we reveal 18 DE-miRNAs that may regulate these DEGs. Among the candidates likely associated with HP pathogenesis was miR-155-5p. Our findings indicate that increased miR-155-5p in fHP fibroblasts coincides with reduced TP53INP1 expression, high proliferative capacity, and a lack of senescence markers compared to IPF fibroblasts. Induced overexpression of miR-155-5p in normal fibroblasts remarkably increases the proliferation rate and decreases TP53INP1 expression. Conversely, miR-155-5p inhibition reduces proliferation and increases senescence markers. TGF-β, IL-4, and IL-17A stimulated miR-155-5p overexpression in HP lung fibroblasts.ConclusionOur findings suggest a distinctive signature of 53 DEGs in HP, including CLDN18, EEF2, CXCL9, PLA2G2D, and ZNF683, as potential targets for future studies. Likewise, 18 miRNAs, including miR-155-5p, could be helpful to establish differences between these two pathologies. The overexpression of miR-155-5p and downregulation of TP53INP1 in fHP lung fibroblasts may be involved in his proliferative and profibrotic phenotype. These findings may help differentiate and characterize their pathogenic features and understand their role in the disease.

Project description:BackgroundToxoplasma gondii is a zoonotic intracellular protozoon that is estimated to infect about 30% of the world's population, resulting in toxoplasmosis in immunocompromised patients and adverse outcomes in cases of primary infection during pregnancy. Exosomes are tubular vesicles secreted by cells, and function in intercellular communication. It has been reported that the exosomes secreted by T. gondii-infected immune cells transmit infection signals to the uninfected cells. However, the mechanism and effect of the exosome transmission are still vague. We therefore investigated the function of the exosomes transmitted from DC2.4 cells infected with the T. gondii RH strain (Tg-DC-Exo) to the uninfected cells, as well as their roles in anti-infection.MethodsWe conducted exosome isolation and identification with ultracentrifugation, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot (WB) analysis. Exosome uptake by recipient cells was identified by PKH67 assay. The signal transmission and the abundance of miR-155-5p were determined using transwell assay and qRT-PCR. For detection of immune responses, cytokine secretion was evaluated. The T. gondii B1 gene was determined to evaluate tachyzoite proliferation.ResultsWe observed that Toxoplasma infection upregulated miR-155-5p expression in DC2.4 cell-secreted exosomes, and those exosomes could be ingested by murine macrophage RAW264.7 cells. Tg-DC-Exo and miR-155-5p stimulated host proinflammatory immune responses including increased production of proinflammatory cytokines IL-6 and TNF-α, and proinflammatory marker-inducible nitric oxide synthase (iNOS). The NF-κB pathway was activated by downregulation of SOCS1, leading to inhibition of T. gondii tachyzoite proliferation in RAW264.7 cells.ConclusionsOur findings provide a novel mechanism for how infected cells transmit infection signals to the uninfected cells through exosome secretion after T. gondii infection, followed by inflammatory responses and anti-infection reactions, which may help us develop a new strategy for toxoplasmosis prevention, especially in immunocompromised patients.

Dataset Information

Testicular exosomes disturb the immunosuppressive phenotype of testicular macrophages mediated by miR-155-5p in uropathogenic Escherichia coli-induced orchitis.

Publications

Testicular exosomes disturb the immunosuppressive phenotype of testicular macrophages mediated by miR-155-5p in uropathogenic <i>Escherichia coli</i>-induced orchitis.

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