MicroRNA-31 Reduces the Motility of Proinflammatory T Helper 1 Lymphocytes.

Markus Bardua,Helena Radbruch,Pawel Durek,Melanie Weber,Mir-Farzin Mashreghi,Mairi Mcgrath,Andreas Radbruch,Katrin Lehmann,Cam Loan Tran,Gitta Anne Heinz,Michael Lohoff,Anna-Barbara Stittrich,Kerstin Westendorf,Hyun-Dong Chang,Claudia Haftmann,Patrick Maschmeyer,Richard Kwasi Addo,Antje Buttgereit

doi:10.3389/fimmu.2018.02813

Abstract

Proinflammatory type 1 T helper (Th1) cells are enriched in inflamed tissues and contribute to the maintenance of chronic inflammation in rheumatic diseases. Here we show that the microRNA- (miR-) 31 is upregulated in murine Th1 cells with a history of repeated reactivation and in memory Th cells isolated from the synovial fluid of patients with rheumatic joint disease. Knock-down of miR-31 resulted in the upregulation of genes associated with cytoskeletal rearrangement and motility and induced the expression of target genes involved in T cell activation, chemokine receptor– and integrin-signaling. Accordingly, inhibition of miR-31 resulted in increased migratory activity of repeatedly activated Th1 cells. The transcription factors T-bet and FOXO1 act as positive and negative regulators of T cell receptor (TCR)–mediated miR-31 expression, respectively. Taken together, our data show that a gene regulatory network involving miR-31, T-bet, and FOXO1 controls the migratory behavior of proinflammatory Th1 cells.

Highlights

Chronic synovial inflammation in rheumatoid arthritis (RA) is dependent on the migration and retention of T cells [1]
As miR-31 has been shown to be expressed in CD4+ [40] and CD8+ T cells upon T cell receptor (TCR) stimulation [25], we aimed to investigate miR-31 expression after repeated antigenic TCR stimulation of murine Th1- cells and in memory Th cells isolated from the inflamed tissue of RA patients
CD3+CD4+CD14−CD45RO+ memory Th cells isolated from the synovial fluid of patients with RA expressed 8.4-fold and 4.9-fold higher levels of miR-31 when compared to their counterparts isolated from the peripheral blood (PB) of healthy subjects (HC) (Figure 1B)

Summary

Introduction

Chronic synovial inflammation in rheumatoid arthritis (RA) is dependent on the migration and retention of T cells [1]. TWIST1 limits inflammation [4] and, at the same time, promotes the survival of Th1 cells in inflamed tissues by up-regulating the microRNA (miR)-148a which targets the pro-apoptotic protein Bim [5, 6]. In T cells, this is mediated by a crosstalk of several signal transduction cascades including the phosphoinositide 3-kinase- (PI3K) signaling pathway activated via TCR and G-protein-coupled receptors (GPCRs), integrin signaling and the Ras homolog gene family- (Rho-) GTPases [11]. It has been shown, that microRNAs interfering with these pathways are able to modulate the motility of lymphocytes [12,13,14]. MicroRNAs might contribute to the persistence of proinflammatory Th1 cells in the inflamed tissues, by moderately and coordinately suppressing several genes involved in these signal transduction pathways [15]

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