Monocytes are essential for inhibition of synovial T-cell glucocorticoid-mediated apoptosis in rheumatoid arthritis

Dimitrios Makrygiannakis,Omri Snir,Cecilia Grundtman,Anca Catrina,Petra Neregård,Shankar Revu,Erik Af Klint

doi:10.1186/ar2582

Dimitrios Makrygiannakis, Omri Snir + Show 5 more

Open Access

https://doi.org/10.1186/ar2582

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Abstract

IntroductionRheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. We previously demonstrated that intra-articular glucocorticoids decrease the synovial tissue (ST) T-cell population and therefore aimed to investigate whether this is mediated through modulation of apoptosis.MethodsApoptosis and cell phenotype were evaluated by immunohistochemistry and dual-immunofluorescence in synovial biopsy sections from 12 RA patients before and after a mean of 11 days of an intra-articular triamcinolone knee injection. In vitro, RA synovial fluid (SF)-derived T cells were evaluated for Annexin V expression by multicolor flow cytometry after 24-hour exposure to dexamethasone, methylprednisolone, or triamcinolone. We also tested induction of apoptosis by dexamethasone on psoriatic arthritis SF-derived T cells using the same method.ResultsIntra-articular glucocorticoids reduced ST T cells but not macrophage number. ST apoptosis levels were unchanged following treatment, virtually absent from lymphoid aggregates, and minimal in CD3+ cells both before and after treatment. RA SF T cells were resistant to glucocorticoid-induced apoptosis when cultured in the presence of monocytes but were rendered sensitive to all three tested compounds upon SF isolation. Furthermore, transwell coculture of monocytes and T cells demonstrated that soluble factor(s) and not cellular contact are essential for T-cell resistance to glucocorticoid-mediated apoptosis. This feature is RA-specific as far as dexamethasone-induced apoptosis in nonisolated SF T cells obtained from psoriatic arthritis patients is concerned.ConclusionsWe demonstrate that monocytes rescue synovial T cells from glucocorticoid-induced apoptosis, a feature that is specific for RA. To overcome this, we propose the use of monocyte-targeted therapies rather than T-cell apoptosis-inducing therapies.

Highlights

Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes
Transwell coculture of monocytes and T cells demonstrated that soluble factor(s) and not cellular contact are essential for T-cell resistance to glucocorticoid-mediated apoptosis
We demonstrate that monocytes rescue synovial T cells from glucocorticoid-induced apoptosis, a feature that is specific for RA

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. It has been suggested that factors such as chronic exposure to tumor necrosis factor (TNF) [5], exposure to interleukin-2 receptor (IL-2R) chain cytokines, and inhibitory signals received through interaction with stromal cells [3] might contribute to the T cell-specific phenotype of the rheumatoid synovium. This phenotype has been associated with the overexpression of two intracellular molecules, Bcl-2 and Bcl-xl [3,6,7], capable of blocking mitochondria-induced apoptosis. Glucocorticoid activities can be divided in (a) genomic effects mediated through cytosolic glucocorticoid receptors (GRs) that need hours to become evident at the cellular and tissue levels and (b) nongenomic effects mediated through membrane-bound GR or nonspecific physicochemical interaction with the cell membrane which might explain some of the immediate effects observed with

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