Distinct expression patterns of TLR transcripts in human oocytes and granulosa cells from primordial and primary follicles

Ernst, Erik; Amoushahi, Mahboobeh; Sørensen, Anne Sofie; Kragstrup, Tue Wenzel; Lykke‐Hartmann, Karin

doi:10.1016/j.jri.2020.103125

Cited by 11 publications

(6 citation statements)

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“…Earlier studies showed that TLR4 is expressed in human cumulus cells. Recently, a study highlighted TLR4 expression in human primordial and primary follicles, with apparent staining in GCs (21). Consistent with these reports, we observed TLR4 expression in mouse GCs at different stages.…”

Section: Discussionsupporting

confidence: 91%

Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-κB Signaling in Human Granulosa Cells

et al. 2021

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Toll-like receptor 4 (TLR4) may play a critical role in regulating follicular development. Data are scarce on the role of TLR4 in the follicle. This study investigated the effects of TLR4 on steroidogenesis in human granulosa cells. Immunohistochemical analysis revealed stage-specific expression of TLR4 in the mouse ovarian cycle, and immunofluorescence showed TLR4 expression in the human granulosa-like tumor cell line (KGN). TLR4 agonist lipopolysaccharides (LPS) significantly inhibited follicular development and synthesis of estradiol (E2) in mice. In KGN cells, TLR4 activation significantly inhibited CYP19A1, FSHR and StAR, and TLR4 inhibition reversed these effects. TLR4 activation also inhibited forskolin-induced secretion of E2 by inhibiting CYP19A1, with no effect on progesterone. Further studies showed activation of p38, JNK and NF-κB signaling after TLR4 activation. Subsequent analyses showed that an NF-κB antagonist reversed the inhibitory effects on CYP19A1 expression and E2 secretion. Together, our results suggest that TLR4 activation may suppress CYP19A1 expression and E2 secretion via NF-κB signaling in human granulosa cells, with important implications for the regulation of ovarian pathophysiology.

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Section: Discussionsupporting

confidence: 91%

Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-κB Signaling in Human Granulosa Cells

et al. 2021

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“… Bukovsky and Presl (1979) reported the association between the immune system and the regulation of ovulation. Mounting reports show that several mediators of LH-induced signaling cascades are associated with inflammation, and the process leading to ovulation and that of the inflammatory response are similar ( Duffy et al, 2019 ; Ernst et al, 2020 ). In the present study, MRP126 was significantly upregulated in the pre-laying period vs. egg-laying period and significantly downregulated in the egg-laying vs. broody period.…”

Section: Discussionmentioning

confidence: 99%

Ovarian transcriptome profile from pre-laying period to broody period of Xupu goose

Qin

Wang

et al. 2021

Poultry Science

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Xupu goose, a breed from Hunan province, produces high quality and quantity of meat and liver. However, its egg production rate is low, with poor reproductive traits but strong broody performance. These characteristics decrease the economic value of Xupu goose significantly. Here, RNA-seq was used to analyze the transcriptome changes of ovaries of Xupu goose at different stages to explore the molecular mechanism of reproduction from the pre-laying period to the broody period. A total of 258 genes were differentially expressed in the 3 stages. These genes are associated with inflammation, reproduction, mutual recognition and adhesion between cells, and cytoskeleton formation, and so on. In particular, we report, for the first time, the expression patterns of MRP126, serglycin, TXNIP, and FZD2 during the pre-laying, egg-laying, and broody periods of goose ovaries. Functional analysis by GO annotation revealed that GO terms were mainly involved in actin, cell signal transduction and regulation, and cellular components. Three pathways, including focal adhesion (gga04510), ECM-receptor interaction (gga04512), and N-Glycan biosynthesis (gga00510), were significantly enriched in the three groups. These findings provide a basis for further exploration of profiles of goose ovaries to improve egg production of Xupu goose.

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“…Mouse cumulus oocyte complexes express TLRs 2, 4, 8 and 9 ( Shimada et al ., 2006 , 2008 ) and abnormal TLRs expression in human cumulus cells has an impact on embryo quality in patients with polycystic ovary syndrome ( Gu et al ., 2016 ). Human oocytes also show expression of TLR proteins ( Ernst et al ., 2020 ), which may be transcribed from maternal stored mRNA, including possibly that transferred across subzonal bridges from the cumulus cells. Another study showed that during maturation of human oocytes, there is a marked alteration in composition of the proteome and secretome which is directed for homeostasis, cellular attachment, and environment interaction ( Virant-Klun et al ., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is not known whether the maternal infection acts solely at the level of an endometrial TLR response, and there has been little consideration of whether early embryos themselves might possess a functional system for recognising and signalling the presence of pathogens in the female tract. A recent study investigated TLR expression in human oocytes and granulosa cells from primordial and primary ovarian follicles and showed that TLR gene expression was positive for TLRs 3, 4 and 5: the authors concluded that human primordial and primary follicles express genes that would provide them with the ability to interact with innate immune proteins during follicle activation ( Ernst et al ., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The expression and activity of Toll-like receptors in the preimplantation human embryo suggest a new role for innate immunity

et al. 2021

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STUDY QUESTION Is the innate immunity system active in early human embryo development? SUMMARY ANSWER The pattern recognition receptors and innate immunity Toll-like receptor (TLR) genes are widely expressed in preimplantation human embryos and the pathway appears to be active in response to TLR ligands. WHAT IS KNOWN ALREADY Early human embryos are highly sensitive to their local environment, however relatively little is known about how embryos detect and respond to specific environmental cues. While the maternal immune response is known to be key to the establishment of pregnancy at implantation, the ability of human embryos to detect and signal the presence of pathogens is unknown. STUDY DESIGN, SIZE, DURATION Expression of TLR family and related genes in human embryos was assessed by analysis of published transcriptome data (n = 40). Day 5 (D-5) human embryos (n = 25) were cultured in the presence of known TLR ligands and gene expression and cytokine production measured compared to controls. PARTICIPANTS/MATERIALS, SETTING, METHODS Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Embryos were cultured to Day 6 (D-6) in the presence of the TLR3 and TLR5 ligands Poly (I: C) and flagellin, with gene expression measured by quantitative PCR and cytokine release into medium measured using cytometric bead arrays. MAIN RESULTS AND THE ROLE OF CHANCE TLR and related genes, including downstream signalling molecules, were expressed variably at all human embryo developmental stages. Results showed the strongest expression in the blastocyst for TLRs 9 and 5, and throughout development for TLRs 9, 5, 2, 6 and 7. Stimulation of Day 5 blastocysts with TLR3 and TLR5 ligands Poly (I: C) and flagellin produced changes in mRNA expression levels of TLR genes, including the hyaluronan-mediated motility receptor (HMMR), TLR5, TLR7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and monocyte chemoattractant Protein-1 (MCP-1) (P < 0.05, P < 0.001 compared to unstimulated controls), and release into culture medium of cytokines and chemokines, notably IL8 (P = 0.00005 and 0.01277 for flagellin and Poly (I: C), respectively). LIMITATIONS, REASONS FOR CAUTION This was a descriptive and experimental study which suggests that the TLR system is active in human embryos and capable of function, but does not confirm any particular role. Although we identified embryonic transcripts for a range of TLR genes, the expression patterns were not always consistent across published studies and expression levels of some genes were low, leaving open the possibility that these were expressed from the maternal rather than embryonic genome. WIDER IMPLICATIONS OF THE FINDINGS This is the first report of the expression and activity of a number of components of the innate immunity TLR system in human embryos. Understanding the role of TLRs during preimplantation human development may be important to reveal immunological mechanisms and potential clinical markers of embryo quality and pregnancy initiation during natural conception and in ART. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the Ministry of Higher Education, The State of Libya, the UK Medical Research Council, and the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility and the European Union’s Horizon 2020 Research and Innovation Programmes under the Marie Skłodowska-Curie Grant Agreement No. 812660 (DohART-NET). In accordance with H2020 rules, no new human embryos were sacrificed for research activities performed from the EU funding, which concerned only in silico analyses of recorded time-lapse and transcriptomics datasets. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER n/a.

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Distinct expression patterns of TLR transcripts in human oocytes and granulosa cells from primordial and primary follicles

Cited by 11 publications

References 55 publications

Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-κB Signaling in Human Granulosa Cells

Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-κB Signaling in Human Granulosa Cells

Ovarian transcriptome profile from pre-laying period to broody period of Xupu goose

The expression and activity of Toll-like receptors in the preimplantation human embryo suggest a new role for innate immunity

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