MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice

Schjenken, John E.; Moldenhauer, Lachlan M.; Zhang, Bihong; Care, Alison S.; Groome, Holly M.; Chan, Hon-Yeung; Hope, Christopher; Barry, Simon C.; Robertson, Sarah A.

doi:10.1038/s41385-020-0255-0

Cited by 33 publications

(29 citation statements)

References 97 publications

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“…In all mammals, the endometrial mucosa has a unique ability to deal with pathogens, allogeneic spermatozoa, and semi-allogeneic embryos ( 1 – 3 ). To achieve this, it seems likely that the uterus is equipped with an efficient and strictly controlled mucosal innate immune system that can differentially respond to these various antigens ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium

et al. 2021

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In mammals, the uterine mucosal immune system simultaneously recognizes and reacts to most bacteria as well as allogenic sperm mainly through the Toll-like receptors (TLR)2/4 signaling pathway. Here, we characterized the impact of pathogen-derived TLR2/4 ligands (peptidoglycan (PGN)/lipopolysaccharide (LPS)) on the immune crosstalk of sperm with the bovine endometrial epithelium. The real-time PCR analysis showed that the presence of low levels of PGN, but not LPS, blocked the sperm-induced inflammatory responses in bovine endometrial epithelial cells (BEECs) in vitro. Immunoblotting analysis revealed that PGN prevented the sperm-induced phosphorylation of JNK in BEECs. Activation or blockade of the TLR2 system in the endometrial epithelium verified that TLR2 signaling acts as a commonly-shared pathway for PGN and sperm recognition. The impairment of endometrial sperm recognition, induced by PGN, subsequently inhibited sperm phagocytosis by polymorphonuclear neutrophils (PMNs). Moreover, using an ex vivo endometrial explant that more closely resembles those in vivo conditions, showed that sperm provoked a mild and reversible endometrial tissue injury and triggered PMN recruitment into uterine glands, while PGN inhibited these events. Of note, PGN markedly increased the sperm attachment to uterine glands, and relatively so in the surface epithelium. However, addition of the anti-CD44 antibody into a PGN-sperm-explant co-culture completely blocked sperm attachment into glands and surface epithelia, indicating that the CD44 adhesion molecule is involved in the PGN-triggered sperm attachment to the endometrial epithelium. Together, these findings demonstrate that, the presence of PGN residues disrupts sperm immune recognition and prevents the physiological inflammation induced by sperm in the endometrial epithelium via the MyD88-dependent pathway of TLR2 signaling, possibly leading to impairment of uterine clearance and subsequent embryo receptivity.

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Section: Introductionmentioning

confidence: 99%

Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium

et al. 2021

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“…Schjenken et al [ 28 ] pointed to the miRNAs as putatively responsible for the underlying mechanisms connecting the SP and the female reproductive immune response, since miRNAs are well-recognized regulators of the immune system [ 26 ]. This hypothesis was confirmed in mice, showing that the SP leads to an increase of several immune-regulatory miRNAs in the endometrium, and highlighting the presence of miR-223, miR-146a and miR-155, all related to immune tolerance [ 17 , 29 ]. Therefore, identifying which miRNAs are involved in modulating the maternal reproductive immune environment would contribute to explaining their role in events related to endometrial receptivity and implantation [ 22 ], processes whose failure may have an immunological basis [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 84%

“…In the pig, it has been demonstrated that miRNAs expressed by the endometrium could play a crucial role for successful embryo implantation and placentation [ 23 , 24 , 25 ]. Given the involvement of miRNAs in the modulation of several immunological pathways [ 26 , 27 , 28 ], it is reasonable to think that miRNAs expressed by the female genital tract could modulate proper maternal immune environment required for successful pregnancy [ 17 , 28 , 29 ]. The miRNAs are not only limited to an intracellular location, since they can be secreted, mainly via extracellular vesicles, to the extracellular environment and then taken up by different cells, modulating its gene transcription [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Seminal Plasma Modulates miRNA Expression by Sow Genital Tract Lining Explants

et al. 2020

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The seminal plasma (SP) modulates the female reproductive immune environment after mating, and microRNAs (miRNAs) could participate in the process. Considering that the boar ejaculate is built by fractions differing in SP-composition, this study evaluated whether exposure of mucosal explants of the sow internal genital tract (uterus, utero-tubal junction and isthmus) to different SP-fractions changed the profile of explant-secreted miRNAs. Mucosal explants retrieved from oestrus sows (n = 3) were in vitro exposed to: Medium 199 (M199, Control) or M199 supplemented (1:40 v/v) with SP from the sperm-rich fraction (SRF), the post-SRF or the entire recomposed ejaculate, for 16 h. After, the explants were cultured in M199 for 24 h to finally collect the media for miRNA analyses using GeneChip miRNA 4.0 Array (Affymetrix). Fifteen differentially expressed (False Discovery Rate (FDR) < 0.05 and Fold-change ≥ 2) miRNAs (11 down- versus 4 up-regulated) were identified (the most in the media of uterine explants incubated with SP from post-SRF). Bioinformatics analysis identified that predicted target genes of dysregulated miRNAs, mainly miR-34b, miR-205, miR-4776-3p and miR-574-5p, were involved in functions and pathways related to immune response. In conclusion, SP is able to elicit changes in the miRNAs profile secreted by female genital tract, ultimately depending SP-composition.

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“…For example, miR-155 could target suppressor of cytokine signaling 1 (SOCS1) to regulate Foxp3 expression and stability, which influenced Treg differentiation and development. 23,24 Other miRNAs, such as miR-146, miR-210, and miR-15a-16, have distinct roles in regulating Treg suppressive function, development, differentiation, and homeostasis via modulating the expression of different target genes. 25 In an effort to better understand other epigenetic factors involved in the mechanism underlying impaired function of Tregs in psoriasis, we focused on the novel member of ncRNAs, circRNAs.…”

Section: Discussionmentioning

confidence: 99%

hsa_circ_0003738 Inhibits the Suppressive Function of Tregs by Targeting miR-562/IL-17A and miR-490-5p/IFN-γ Signaling Pathway

Yang

Zhang

Bai

et al. 2020

Molecular Therapy - Nucleic Acids

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Dysfunction in the suppressive function of regulatory T cells (Tregs) has been related to the pathogenesis of psoriasis. Accumulating evidence has demonstrated the importance of circular RNAs (circRNAs) in regulating various biological process, such as cell proliferation, apoptosis, etc. However, the role of circR-NAs in modulating the suppressive functions of psoriatic Tregs and the underlying mechanisms have not been investigated. Here, by using circRNA microarray analysis, we discovered four upregulated and four downregulated circRNAs in psoriatic Tregs. Quantitative real-time PCR further confirmed a significant increase of circ_0003738 in psoriatic Tregs. Importantly, knockdown of circ_0003738 by lentivirus in psoriatic Tregs could restore their suppressive functions via inhibiting the secretion of proinflammatory cytokines interleukin-17A (IL-17A) and interferon (IFN)-g. Moreover, we found that circ_0003738 could bind to miR-562 to release the inhibition of target gene IL-17RA (IL-17 receptor A), thus promoting IL-17A signaling in psoriatic Tregs. In parallel, circ_0003738 acted also as a sponge for miR-490-5p and relieved inhibition for the target gene IFNGR2, which promoted IFN-g signaling in psoriatic Tregs. Our study demonstrated that upregulated circ_0003738 decreased the suppressive function of psoriatic Tregs via the miR-562/IL17RA and miR-490-5p/IFNGR2 (IFN-g receptor 2) axis, which indicated the involvement of circRNAs in the pathogenesis of dysfunctional Tregs. These findings will provide new therapeutic targets for the treatment of psoriasis.

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MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice

Cited by 33 publications

References 97 publications

Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium

Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium

Seminal Plasma Modulates miRNA Expression by Sow Genital Tract Lining Explants

hsa_circ_0003738 Inhibits the Suppressive Function of Tregs by Targeting miR-562/IL-17A and miR-490-5p/IFN-γ Signaling Pathway

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