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Dysregulation of miRNA-30e-3p targeting IL-1β in an international cohort of systemic autoinflammatory disease patients

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Abstract

Autoinflammation is the standard mechanism seen in systemic autoinflammatory disease (SAID) patients. This study aimed to investigate the effect of a candidate miRNA, miR-30e-3p, which was identified in our previous study, on the autoinflammation phenotype seen in SAID patients and to analyze its expression in a larger group of European SAID patients. We examined the potential anti-inflammatory effect of miR-30e-3p, which we had defined as one of the differentially expressed miRNAs in microarray analysis involved in inflammation-related pathways. This study validated our previous microarray results of miR-30e-3p in a cohort involving European SAID patients. We performed cell culture transfection assays for miR-30e-3p. Then, in transfected cells, we analyzed expression levels of pro-inflammatory genes; IL-1β, TNF-α, TGF-β, and MEFV. We also performed functional experiments, caspase-1 activation by fluorometric assay kit, apoptosis assay by flow cytometry, and cell migration assays by wound healing and filter system to understand the possible effect of miR-30e-3p on inflammation. Following these functional assays, 3'UTR luciferase activity assay and western blotting were carried out to identify the target gene of the aforementioned miRNA. MiR-30e-3p was decreased in severe European SAID patients like the Turkish patients. The functional assays associated with inflammation suggested that miR-30e-3p has an anti-inflammatory effect. 3'UTR luciferase activity assay demonstrated that miR-30e-3p directly binds to interleukin-1-beta (IL-1β), one of the critical molecules of inflammatory pathways, and reduces both RNA and protein levels of IL-1β. miR-30e-3p, which has been associated with IL-1β, a principal component of inflammation, might be of potential diagnostic and therapeutic value for SAIDs.

Key Messages

  • miR-30e-3p, which targets IL-1β, could have a role in the pathogenesis of SAID patients.

  • miR-30e-3p has a role in regulating inflammatory pathways like migration, caspase-1 activation.

  • miR-30e-3p has the potential to be used for future diagnostic and therapeutic approaches.

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Availability of data and materials

The graphical abstract was created with BioRender.com. The microarray data generated or analyzed during this study are included in this published article [14], but are available from the corresponding author on reasonable request.

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Funding

This work was supported by ERARE3 project (INSAID, grant number 003037603) and The Technical and Scientific Research Council of Turkey (TUBITAK), Grant number: 315S096. Three centers involved in this publication (IRCCS Istituto Giannina Gaslini of Genoa, University Hospital of Munster, and University Medical Center of Groninger) are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases - Project ID No 739543.

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Tayfun Hilmi Akbaba, Yeliz Z. Akkaya-Ulum & Banu Balci-Peynircioglu

  2. Department of Pediatric Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Ezgi Deniz Batu & Seza Ozen

  3. Unit of Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, Genova, Italy

    Federica Penco

  4. Department for Pediatric Rheumatology & Immunology, University Hospital Muenster, Muenster, Germany

    Helmut Wittkowski & Dirk Foell

  5. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands

    Benjamin Kant, Marielle E. van Gijn & Marco Gattorno

  6. Department of Genetics, University Medical Center Groningen, Groningen, Netherlands

    Marielle E. van Gijn

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  1. Tayfun Hilmi Akbaba
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Contributions

THA, ZYAU, SO, and BBP: conceptualization. THA and ZYAU: investigation. EDB, FP, HW, BK, MEVG, DF, MG, and SO: resources. THA and BBP: writing the original draft. THA, EDB, BBP, and SO: writing the review and editing. MEVG, DF, MG, SO, and BBP: funding acquisition. The authors have read and approved the final manuscript.

Corresponding author

Correspondence to Banu Balci-Peynircioglu.

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The study was approved by the Hacettepe University Non-Interventional Clinical Research Ethics Board (GO 15/1744–19). Written consent was obtained from all parents and children.

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Akbaba, T.H., Akkaya-Ulum, Y.Z., Batu, E.D. et al. Dysregulation of miRNA-30e-3p targeting IL-1β in an international cohort of systemic autoinflammatory disease patients. J Mol Med 101, 757–766 (2023). https://doi.org/10.1007/s00109-023-02327-2

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