Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice.

Jürgen Dieker,Henry Dijkman,Johan van der Vlag,Luuk Hilbrands,Jo H Berden,Astrid Thielen

doi:10.1186/s13075-015-0617-2

Jürgen Dieker, Henry Dijkman + Show 4 more

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https://doi.org/10.1186/s13075-015-0617-2

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Abstract

IntroductionSystemic lupus erythematosus is associated with a persistent circulation of modified autoantigen-containing apoptotic debris that might be capable of breaking tolerance. We aimed to evaluate apoptotic microvesicles obtained from lupus or control mice for the presence of apoptosis-associated chromatin modifications and for their capacity to stimulate dendritic cells (DC) from lupus and control mice.MethodApoptotic microvesicles were in vitro generated from splenocytes, and ex vivo isolated from plasma of both MRL/lpr lupus mice and normal BALB/c mice. Microvesicles were analyzed using flow cytometry. Bone marrow-derived (BM)-DC cultured from MRL/lpr or BALB/c mice were incubated with microvesicles and CD40 expression and cytokine production were determined as measure of activation.ResultsMicrovesicles derived from apoptotic splenocytes or plasma of MRL/lpr mice contained more modified chromatin compared to microvesicles of BALB/c mice, and showed enhanced activation of DC, either from MRL/lpr or BALB/c mice, and consecutively an enhanced DC-mediated activation of splenocytes. The content of apoptosis-modified chromatin in microvesicles of apoptotic splenocytes correlated with their potency to induce interleukin-6 (IL-6) production by DC. Microvesicle-activated MRL/lpr DC showed a significant higher production of IL-6 and tumor growth factor-β (TGF-β) compared to BALB/c DC, and were more potent in the activation of splenocytes.ConclusionApoptotic microvesicles from MRL/lpr mice are more potent activators of DC, and DC from MRL/lpr mice appear relatively more sensitive to activation by apoptotic microvesicles. Our findings indicate that aberrations at the level of apoptotic microvesicles and possibly DC contribute to the autoimmune response against chromatin in MRL/lpr mice.

Highlights

Systemic lupus erythematosus is associated with a persistent circulation of modified autoantigencontaining apoptotic debris that might be capable of breaking tolerance
Microvesicles derived from apoptotic splenocytes or plasma of MRL/lpr mice contained more modified chromatin compared to microvesicles of BALB/c mice, and showed enhanced activation of dendritic cells (DC), either from MRL/lpr or BALB/c mice, and consecutively an enhanced DC-mediated activation of splenocytes
The content of apoptosismodified chromatin in microvesicles of apoptotic splenocytes correlated with their potency to induce interleukin-6 (IL-6) production by DC

Summary

Introduction

Systemic lupus erythematosus is associated with a persistent circulation of modified autoantigencontaining apoptotic debris that might be capable of breaking tolerance. We aimed to evaluate apoptotic microvesicles obtained from lupus or control mice for the presence of apoptosis-associated chromatin modifications and for their capacity to stimulate dendritic cells (DC) from lupus and control mice. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by high levels of autoantibodies against chromatin [1]. Disturbances in apoptosis and the removal of apoptotic cells, leading to the persistent presence of apoptotic debris in the circulation, have been associated with the development of SLE in patients and in mouse models [2,3]. Apoptosis involves the translocation of chromatin from the nucleus into MVs (MVs) at the cell surface. The exposure of DC to different types of apoptotic cells may guide the immune response

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