<i>Toxoplasma gondii</i> excreted‐secreted antigens suppress Foxp3 promoter activity via a SP1‐dependent mechanism

Chen, Jinling; Wang, Jingjing; Gao, Xuyang; Zhu, Dandan; Chen, Liuting; Duan, Yinong

doi:10.1111/jcmm.15703

Cited by 4 publications

(4 citation statements)

References 42 publications

(96 reference statements)

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“…T. gondii infection-induced adverse outcomes are primarily correlated to the disruption of immune tolerance rather than the replication of T. gondii [ 25 ]. ESA was often used to explore the mechanism of maternal–fetal immune imbalance in in vivo and in vitro studies [ 6 , 18 , 26 ]. T. gondii lysate antigens (TLA) do trigger the immune response, which induces increased levels of IL-10 and TGF-β in BV-2 microglial cultured in vitro [ 27 ] .…”

Section: Discussionmentioning

confidence: 99%

“…Multiple miRNAs are shown to modulate cell development and function, which mainly inhibit the expressions of Foxp3 and other related genes via binding to mRNA 3′UTR. miR-133a-3p inhibits Foxp3 expression by binding to Foxp3 3′ UTR, thereby promoting proliferation and autophagy in gastric cancer cells [ 18 ]. miR-7 can directly bind to the 3′ UTR of T-cell acute lymphocytic leukemia protein 1 (TAL1) to suppress the migration, invasion, and cell motility of T-cell acute lymphoblastic leukemia cells, which can be reversed by TAL1 overexpression [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Transcription factors directly regulate Foxp3 gene expression by targeting its promoters [ 55 ]. Our previous study revealed that T. gondii antigens suppress the promoter activity of Foxp3 via an Sp1 dependency mechanism [ 18 ]. In this present study, our data further revealed that T. gondii antigens could facilitate miR-7b to inhibit Sp1 expression by targeting the Sp1 3' UTR, thereby inversely regulating Foxp3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we report that both T. gondii and antigens increased miR-7b level but decreased Foxp3 expression. Additionally, our previous study revealed that T. gondii antigens affect the promoter activity of Foxp3 via an Sp1-dependent mechanism [ 18 ]. T. gondii ESA promotes miR-7b promoter activity in a PPARγ-dependent manner, inhibits specific protein 1 (Sp1) expression via targeting Sp1 3' UTR, and thereby represses Foxp3 expression.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Foxp3 expression in the placenta of mice infected intraperitoneally by toxoplasma gondii tachyzoites: insights into the PPARγ/miR-7b-5p/Sp1 signaling pathway

Zhong,

Qin,

Wang

et al. 2024

Parasites Vectors

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Background Toxoplasma gondii, an obligate intracellular parasitic protozoa, infects approximately 30% of the global population. Contracting T. gondii at the primary infection of the mother can result in neonatal microcephaly, chorioretinitis, hydrocephalus, or mortality. Our previous study indicated that pregnant mice infected with T. gondii displayed a decrease in both the number and the suppressive ability of regulatory T cells, accompanied by the reduced Forkhead box P3 (Foxp3). Numerous studies have proved that microRNAs (miRNAs) are implicated in T. gondii infection, but there is meager evidence on the relationship between alterations of miRNAs and downregulation of Foxp3 induced by T. gondii. Methods Quantitative reverse transcription polymerase chain reaction was utilized to detect the transcriptions of miRNAs and Foxp3. Protein blotting and immunofluorescence were used to detect the expressions of Foxp3 and related transcription factors. The structure of mouse placenta was observed by hematoxylin and eosin (HE) staining. To examine the activity of miR-7b promoter and whether miR-7b-5p targets Sp1 to suppress Foxp3 expression, we constructed recombinant plasmids containing the full-length/truncated/mutant miR-7b promoter sequence or wildtype/mutant of Sp1 3' untranslated region (3' UTR) to detect the fluorescence activity in EL4 cells. Results In T. gondii-infected mice, miR-7b transcription was significantly elevated, while Foxp3 expression was decreased in the placenta. In vitro, miR-7b mimics downregulated Foxp3 expression, whereas its inhibitors significantly upregulated Foxp3 expression. miR-7b promoter activity was elevated upon the stimulation of T. gondii antigens, which was mitigated by co-transfection of mutant miR-7b promoter lacking peroxisome proliferator-activated receptor γ (PPARγ) target sites. Additionally, miR-7b mimics diminished Sp1 expression, while miR-7b inhibitors elevated its expression. miR-7b mimics deceased the fluorescence activity of Sp1 3' untranslated region (3' UTR), but it failed to impact the fluorescence activity upon the co-transfection of mutant Sp1 3' UTR lacking miR-7b target site. Conclusions T. gondii infection and antigens promote miR-7b transcription but inhibit Foxp3 protein and gene levels. T. gondii antigens promote miR-7b promoter activity by a PPARγ-dependent mechanism. miR-7b directly binds to Sp1 3' UTR to repress Sp1 expression. Understanding the regulatory functions by which T. gondii-induced miR-7b suppresses Foxp3 expression can provide new perspectives for the possible therapeutic avenue of T. gondii-induced adverse pregnancy outcomes. Graphical Abstract

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