Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory diseases

Snyder, Brittany L.; Blackshear, Perry J.

doi:10.1016/j.pharmthera.2022.108198

Cited by 11 publications

(8 citation statements)

References 153 publications

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“… 50 ZFP36 is a small group of mRNA binding and destabilizing proteins expressed in almost all eukaryotes. 51 A previous bioinformatics analysis study suggests that ZFP36 may be an endothelial cell senescence-related gene in patients with MI. 52 Li et al also found significantly elevated ZFP36 protein levels in ischemic human heart tissue and knockdown of ZFP36 in HCMECs using siRNA significantly inhibited cell proliferation.…”

Section: Discussionmentioning

confidence: 97%

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction

Ke,

Ni,

Yuan

et al. 2024

JIR

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Purpose Studies have shown that neutrophil-mediated formation of neutrophil extracellular traps (NETs) leads to increased inflammatory response and cellular tissue damage during myocardial infarction (MI). We aimed to identify and validate possible hub genes in the process of NETs-mediated cell damage. Methods We performed an immune cell infiltration analysis of the MI transcriptome dataset based on CIBERSORT and ssGSEA algorithms. Gene expression profiles of NETs formation (GSE178883) were used to analyze the physiological processes of peripheral blood neutrophils after phorbol myristate acetate (PMA) stimulation. Bioinformatics and machine learning algorithms were utilized to find candidate hub genes based on NETs-related genes and transcriptome datasets (GSE66360 and GSE179828). We generated the receiver operating curve (ROC) to evaluate the diagnostic value of hub genes. Next, the correlation between hub genes and immune cells was analyzed using CIBERSORT, ssGSEA and xCell algorithms. Finally, we used quantitative real-time PCR (qRT-PCR) and immunohistochemistry to verify gene expression. Results Immune cell infiltration analysis revealed that inflammatory cells such as neutrophils were highly expressed in the peripheral blood of patients with MI. Functional analysis of differentially expressed genes (DEGs) in GSE178883 indicated that the potential pathogenesis lies in immune terms. Using weighted gene co-expression network analysis (WGCNA) and machine learning algorithms, we finally identified the seven hub genes (FCAR, IL1B, MMP9, NFIL3, CXCL2, ICAM1, and ZFP36). The qRT-PCR results showed that IL-1B, MMP9, and NFIL3 mRNA expression was up-regulated in the MI group compared to the control. Immunohistochemical results showed high MMP9, IL-1B, and NFIL3 expression in the infarcted area compared to the non-infarcted area and sham-operated groups. Conclusion We identified seven hub genes associated with NETs-mediated cellular damage during MI. Our results may provide insights into the mechanisms of neutrophil-mediated cell injury during MI.

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Section: Discussionmentioning

confidence: 97%

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction

Ke,

Ni,

Yuan

et al. 2024

JIR

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“…TTP or ZFP36 has been implicated in playing key roles in inflammatory diseases such as RA, and overexpression of TTP throughout the body that can mitigate the inflammation response in models of experimental arthritis [ 2 ] and other inflammatory disease models (reviewed in [ 2 , 13 ]. We focused on the role of TTP overexpression in the hematopoietic stem and progenitor cells in young and middle-aged mice and determined the exclusive expression of TTPΔARE in hematopoietic cells could lead to the mitigation of inflammation challenge in middle-aged mice.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that increased stability of TTP can confer protection against inflammatory responses in various mouse models of human disease, including RA, psoriasis, multiple sclerosis, and others [ 2 , 13 ] but it is unclear how the increased TTP affects the early hematopoietic progenitor compartment, and whether the mitigation of inflammation is exclusively driven by the hematopoietic compartment. Using the TTPΔARE mouse model, we examined the effects of overexpression of this mRNA decay regulator on the hematopoietic system, with a focus on primitive BM populations, and determine that even low frequencies of hematopoietic cells overexpressing TTP will exert a dominant effect of mitigating inflammatory responses in collagen antibody-induced arthritis (CAIA).…”

Section: Introductionmentioning

confidence: 99%

Tristetraprolin overexpression drives hematopoietic changes in young and middle-aged mice generating dominant mitigating effects on induced inflammation in murine models

et al. 2023

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Tristetraprolin (TTP), encoded by Zfp36 in mice, is one of the best-characterized tandem zinc-finger mRNA binding proteins involved in mRNA deadenylation and decay. TTPΔARE mice lack an AU-rich motif in the 3′-untranslated regions of TTP mRNA, leading to increased TTP mRNA stability and more TTP protein, resulting in elevated mRNA decay rates of TTP targets. We examined the effect of TTP overexpression on the hematopoietic system in both young and middle-aged mice using TTPΔARE mice and found alterations in blood cell frequencies, with loss of platelets and B220 cells and gains of eosinophils and T cells. TTPΔARE mice also have skewed primitive populations in the bone marrow, with increases in myeloid-biased hematopoietic stem cells (HSCs) but decreases in granulocyte/macrophage-biased multipotent progenitors (MPP3) in both young and middle-aged mice. Changes in the primitive cells’ frequencies were associated with transcriptional alterations in the TTP overexpression cells specific to age as well as cell type. Regardless of age, there was a consistent elevation of transcripts regulated by TNFα and TGFβ signaling pathways in both the stem and multipotent progenitor populations. HSCs with TTP overexpression had decreased reconstitution potential in murine transplants but generated hematopoietic environments that mitigated the inflammatory response to the collagen antibody-induced arthritis (CAIA) challenge, which models rheumatoid arthritis and other autoimmune disorders. This dampening of the inflammatory response was even present when there was only a small frequency of TTP overexpressing cells present in the middle-aged mice. We provide an analysis of the early hematopoietic compartments with elevated TTP expression in both young and middle-aged mice which inhibits the reconstitution potential of the HSCs but generates a hematopoietic system that provides dominant repression of induced inflammation.

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“…Furthermore, the NF-κB signaling pathway has been shown to be inhibited by MiR-223, and this can delay cancer cell proliferation 24 and is closely related to immune regulation as well. 35 However, results acquired from computational analysis typically require further validation through wet-lab testing, such as qPCR experiments, which we also performed. In our qPCR results, we found that MiR-223 showed a high expression status in the villous tissues of EP and significant differences between the experiment and control groups.…”

Section: Discussionmentioning

confidence: 99%

Identification of MiR-223 Associated with Diagnosis in Ectopic Pregnancy

Qiu¹,

Chen²,

Deng³

et al. 2023

IJGM

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Background In this study, we conducted an integrated study of the diagnostic value of MiR-223 in ectopic pregnancy (EP). Methods We used GSE44731 downloaded from GEO and GEO2R to identify differentially expressed miRNA. The hub genes corresponding to the differential miRNA were then identified by using the Xiantao academic tool, GO (Gene Ontology), and KEGG (Kyoto Encyclopedia of Genes and Genomes). Afterward, we used the miEAA database to perform gene set enrichment analysis (GSEA) of differential miRNA, and used Xiantao academic tools again to conduct the ceRNA network based on the target genes. Protein–protein interaction (PPI) network construction and lncRNA of hub miRNA target genes were then predicted by the starbase database. For validation, the villus tissue from intrauterine pregnancy and tubal pregnancy was collected and assayed by qPCR. Results In total 19 differentially expressed miRNAs were screened out, of which MiR-223 had a relatively clear diagnostic significance. Hub genes were enriched and analyzed by GO, KEGG, and GSEA, and the results showed that regulation of NF-κB and other signaling pathways are primarily enriched in ectopic pregnancy. We also obtained 215 key genes from PPI analysis. Our ceRNA analysis indicated that LRRC75A-AS1 and PITPNA-AS1 were associated with MiR-223, and the expression of MiR-223 in qPCR was significantly high in tubal pregnancy group. Conclusion We found that MiR-223 can be used in the diagnosis of EP. Our findings provide valuable information and direction for future research into novel targets for EP diagnosis.

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Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory diseases

Cited by 11 publications

References 153 publications

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction

Tristetraprolin overexpression drives hematopoietic changes in young and middle-aged mice generating dominant mitigating effects on induced inflammation in murine models

Identification of MiR-223 Associated with Diagnosis in Ectopic Pregnancy

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