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Abstract Number: 972

JAK/STAT Mediated Inhibition of Mir-23a~24-2~27a Cluster Potentiates Activation of CD14+ Monocytes in Treatment-Resistant RA

Marina Frleta-Gilchrist, Donna McIntyre, Aziza Elmesmari, Lynn Stewart, Derek Baxter, Mariola Kurowska-Stolarska, Derek Gilchrist and Iain B. McInnes, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: IL-6R signaling, Janus kinase (JAK), MicroRNA, rheumatoid arthritis (RA) and treatment options

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Session Information

Date: Monday, November 6, 2017

Title: Cytokines, Mediators, Cell-Cell Adhesion, Cell Trafficking and Angiogenesis Poster II: Mesenchymal Cells Do React - But How?

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

While emerging and existing treatments of RA allow better options and clinical outcomes for patients, studies informing drug resistant states and further clinical therapeutic choices are lagging. We sought herein to compare a cross-sectional cohort of patients with maintained low disease activity on conventional DMARDs (cDMARDs) and patients failing multiple modes of both conventional or biologic treatments. A broad insight into the treatment resistant state was obtained by selecting blood derived CD14+ cells as precursors of many pathogenic cell types in RA. From these, we profiled the expression of microRNAs (miR), which as post-transcriptional regulators have the ability to control entire pathways giving an informative ‘snapshot’ of cell state. The resulting data identified regulatory miRs and associated pro-inflammatory pathways underpinning treatment resistance in RA, highlighting how they could be utilized to inform future treatment choices.

Methods:

RA patients meeting ACR 2010 diagnostic criteria were selected for this study. Two control groups included 21 healthy matched controls and 16 patients with established disease, well controlled by conventional DMARDs (cDMARDs); while treatment resistant groups contained 22 patients with high disease activity with cDMARDs and 41 patients with active disease after multiple biologic agents. Peripheral blood CD14+ cells were isolated using Miltenyi isolation kit. MiR expression was determined using the Affymetrix 3.0 miR Array. Predicted miR targets were identified using TargetScan. Direct miR-target interactions were confirmed by luciferase reporter assay. CD14+ cells isolated from buffy coats were stimulated with IL-6, IFNγ or GM-CSF. THP-1 cell lines lacking the activities of miR-23a, miR-27a singly or together were created by the stable introduction of miR sponge transgenes.

Results:

Microarray profiling of CD14+ cells from patient cohort showed that the expression of miR-23a~24-2~27a cluster was significantly repressed in both treatment resistant RA groups. Specifically, miR-23a and miR-27a were found to mediate a novel regulatory feedback loop of the IL-6 pathway. IL-6 stimulation of primary monocytes suppressed the expression of these miRs. In turn, this alleviated the repression of their direct targets, both soluble and membrane bound IL-6R, further sensitizing the cells to IL-6 signaling. Additionally, miR-23a and miR-27a expression was repressed by other cytokines utilizing JAK/STAT signaling cascade, such as viral mediator IFNγ, but also monocyte maturation factor GM-CSF, suggesting a potential mechanism for their activation upon migration into tissues. Moreover, cells lacking miR-23a and miR-27a expressed higher levels of the pro-inflammatory cytokines TNFα and IL-6 upon LPS stimulation.

Conclusion:

Collectively, these data provide evidence of how the multifactorial induction of intracellular JAK/STAT signaling inhibits miR-23a cluster expression leading to increased production of IL-6R, further potentiating the role of this novel pro-inflammatory circuit in treatment resistant RA.


Disclosure: M. Frleta-Gilchrist, None; D. McIntyre, None; A. Elmesmari, None; L. Stewart, None; D. Baxter, None; M. Kurowska-Stolarska, None; D. Gilchrist, None; I. B. McInnes, None.

To cite this abstract in AMA style:

Frleta-Gilchrist M, McIntyre D, Elmesmari A, Stewart L, Baxter D, Kurowska-Stolarska M, Gilchrist D, McInnes IB. JAK/STAT Mediated Inhibition of Mir-23a~24-2~27a Cluster Potentiates Activation of CD14+ Monocytes in Treatment-Resistant RA [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/jakstat-mediated-inhibition-of-mir-23a24-227a-cluster-potentiates-activation-of-cd14-monocytes-in-treatment-resistant-ra/. Accessed .
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