Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease

Zitzer, Nina C.; Garzon, Ramiro; Ranganathan, Parvathi

doi:10.3389/fimmu.2018.02561

Cited by 11 publications

(8 citation statements)

References 91 publications

(83 reference statements)

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“…Lymphocytes may migrate to secondary lymphoid organs for further maturation and activation, which then led to secretion of proinflammatory cytokines causing subsequent an inflammatory storm and tissue damages. This inflammatory infiltration and destruction thereby induce aGvHD, leading to transplant failure and even death [ 1 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells

Liu¹,

Zhou

Liu³

et al. 2021

Stem Cell Res Ther

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Background Mesenchymal stem cells (MSCs) have been utilized in treating acute graft-versus-host disease (aGvHD) as they show strong immunosuppressive capacity through the release of various mediators, including immunosuppressive molecules, growth factors, chemokines, and exosomes. MicroRNAs (miRNAs) derived from MSC exosomes (MSCs-Exo) play a critical role in the regulation of immune responses. However, the function of miRNAs in treating aGvHD remains unknown. Here, we performed expression profiling of exosome-miRNAs from human umbilical cord MSCs (huc-MSCs) and murine compact bone MSCs (mb-MSCs) to investigate their immunoregulation effects in aGvHD. Methods Huc-MSCs-Exo and mb-MSCs-Exo were isolated and constructed MSCs-Exo-derived miRNA expression profiling using high-throughput sequencing. High expression of miR-223 was identified in both kinds of MSCs-Exo by bioinformatics analysis and quantitative real-time PCR (qPCR). In vitro cell crawling assay, transmigration assay and adhesion assay were subsequently applied to investigate the regulation of miR-223 on T cells. MiR-223 target gene was analyzed by western blot, luciferase analysis, and qPCR. Moreover, murine aGvHD model was established by infusing splenocytes and bone marrow nuclear cells from C57BL/6j mice (H-2Kb) into BALB/c recipient mice (H-2Kd). For therapeutic effect, MSCs or miR-223 Agomir were injected via tail vein. The general conditions of the mice in each group were monitored. Hematoxylin-eosin (H&E) staining was used to detect pathological changes of mice spleen, liver, and intestine. Mechanistically, immunofluorescence and flow cytometry were used to evaluate donor T cell migration, and enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of serum inflammatory cytokines IFN-γ, TNF-α, and IL-17. Results High-throughput sequencing revealed high expression of miR-223 in huc-MSCs-Exo and mb-MSCs-Exo. MiR-223 could restrain adhesion and migration of T cells by inhibiting ICAM-1 expression in mouse lymphatic endothelial cells. MiR-223Agomir infusion attenuated aGvHD clinical symptoms, reduced the donor T cell infiltration into the spleen, liver, and intestine, and decreased inflammatory cytokines IFN-γ, TNF-α, and IL-17. Conclusion MSCs-Exo-derived miR-223 could attenuate aGvHD in mice through decreasing donor T cell migration. Our results unveil a new role of MSCs-Exo containing miR-223 in the treatment of aGvHD.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells

Liu¹,

Zhou

Liu³

et al. 2021

Stem Cell Res Ther

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“…lymphocytes may migrate to secondary lymphoid organs for further maturation and activation, which then led to secretion of proinflammatory factors causing subsequent an inflammatory storm and tissue damages. This inflammatory infiltration and destruction thereby induce aGvHD, leading to transplant failure and even death [2,36].…”

Section: Discussionmentioning

confidence: 99%

MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

Liu¹,

Zhou²,

Wang³

et al. 2020

Preprint

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Background Mesenchymal stem cells (MSCs) have been utilized in treating acute graft-versus-host disease (aGvHD) as they show strong immunosuppressive capacity, but the mechanisms are not well defined.Methods In this study, we demonstrated that microRNA-223 (miR-223) derived from exosomes secreted by human umbilical cord mesenchymal stem cells (huc-MSCs) and murine compact bone mesenchymal stem cells (mb-MSCs) could inhibit aGvHD progression by reducing the migration and homing of donor T cells in aGvHD mice.Results MiR-223 was one of the conserved microRNAs highly expressed in huc-MSCs exosomes and mMSCs exosomes, which was identified by high-throughput sequencing. MiR-223 derived from MSC exosomes showed enhanced immunosuppressive capacity, as it could inhibit expression of the target gene ICAM-1 and restrain adhesion and migration of T cells in vitro. Moreover, miR-223Agomir was effective in reducing the inflammatory reaction, and declining the donor T cells infiltration into the spleen, liver and intestine in aGvHD mice. Subsequently, it could alleviate aGvHD symptoms. Taken together, the MSC exosome derived miR-223 could attenuate aGvHD in mice through regulating ICAM-1 expression.Conclusions Our results unveil a new role for MSC exosomes derived miR-223 in the treatment of aGvHD.

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“…Using the murine model of aGVHD, it was elucidated that the downregulation of this miRNA with locked nucleic acid anti-miR-29a resulted in a clinically significant improvement in the survival and reduction of aGVHD severity, without impairment of graft-versus-leukemia effects [68]. The TLR signaling pathway activates MyD88-dependent transcription factors, including IRF7 and NF-kB [69]. MiR-29a stimulation causes translocation of both NF-kB-p65 and IRF7 phosphorylated into the cellular nucleus [68].…”

Section: Circulating Micrornas As Predictive Biomarkers Of Agvhdmentioning

confidence: 99%

MicroRNAs as Potential Diagnostic, Prognostic, and Predictive Biomarkers for Acute Graft-versus-Host Disease

Motaei

Yaghmaie

Ahmadvand

et al. 2019

Biology of Blood and Marrow Transplantation

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Successful treatment of various hematologic diseases with allogeneic hematopoietic stem cell transplantation is often limited due to the occurrence of acute graft-versus-host disease (aGVHD). So far, there are no approved molecular biomarkers for the diagnosis and prediction of aGVHD at the clinical level due to our incomplete understanding of the molecular biology of the disease. Various studies have been conducted on animal models and humans to investigate the role of microRNAs in aGVHD pathogenesis to implicate them as biomarkers and therapeutic targets. Because of their high stability, tissue specificity, ease of measurement, low cost, and simplicity, they are excellent targets for biomarkers. In this review, we focused on microRNA expression profiling studies that were performed recently in both animal models and human cases of aGVHD to identify diagnostic and predictive biomarkers for this disease. The expression pattern of microRNAs can be specific to cells and tissues. Because aGVHD affects several organs, microRNA signatures in target tissues may help to understand the molecular pathology of the disease. Identification of organ-specific microRNAs in aGVHD can be promising to categorize patients for organ-specific therapies. Thus, microRNAs can be used as noninvasive diagnostic tests in clinic to improve prophylaxis, predict incidence and severity, and reduce morbidity.

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Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease

Cited by 11 publications

References 91 publications

Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells

Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells

MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

MicroRNAs as Potential Diagnostic, Prognostic, and Predictive Biomarkers for Acute Graft-versus-Host Disease

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