Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide

Frontiers in Immunology
Stephanie R HarrisonSinisa Savic

Abstract

Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB). In this study, we hypothesized that proinflammatory cytokine signaling in TRAPS downregulates these two miRs, resulting in LPS-induced hyperresponsiveness in TRAPS dermal fibroblasts (DFs), irrespective of the underlying genetic mutation. Primary DF were isolated from skin biopsies of TRAPS patients and healthy controls (HC). TNFR1 cell surface expression was measured using immunofluorescence. DF were stimulated with LPS, interleukin (IL)-1β, thapsigargin, or TNF, with and without inositol-requiring enzyme 1 (IRE1) inhibitor (4u8C), following which miR-146a and miR-155 expression was measured by RT-qPCR. IL-1β, IL-6, and TNF secretion was measured by enzyme-linked immunosorbent assays, and baseline express...Continue Reading

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Citations

May 31, 2019·Current Opinion in Rheumatology·Amandine Charras, Christian M Hedrich
Apr 19, 2020·Der Hautarzt; Zeitschrift für Dermatologie, Venerologie, und verwandte Gebiete·E RolfesT Kallinich
Feb 23, 2020·Mediators of Inflammation·Carla GaggianoLuca Cantarini
May 10, 2020·International Journal of Molecular Sciences·Cornelia CudriciIvona Aksentijevich

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Datasets Mentioned

BETA
GSE109363

Methods Mentioned

BETA
biopsies
Enzyme-Linked Immunosorbent

Software Mentioned

MikroWin 2000
Cluster
DIANA miRpath
AxioVision Rel
Java Tree View

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