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Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice
Jürgen Dieker1, Luuk Hilbrands2, Astrid Thielen3
1Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. jurgen.dieker@radboudumc.nl.
Introduction:
Systemic 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.
Method:
Apoptotic 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.
Results:
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 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.
Conclusion:
Apoptotic 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.
Insights
Apoptotic microvesicles from lupus mice show increased chromatin modifications, leading to enhanced dendritic cell activation and potentially driving autoimmune responses in systemic lupus erythematosus.
Area of Science:
- Immunology
- Cell Biology
Background:
- Systemic lupus erythematosus (SLE) involves persistent circulation of modified autoantigen-containing apoptotic debris.
- These debris may break immune tolerance, contributing to autoimmunity.
Purpose of the Study:
- To evaluate chromatin modifications in apoptotic microvesicles from lupus and control mice.
- To assess the capacity of these microvesicles to stimulate dendritic cells (DCs) from lupus and control mice.
Main Methods:
- In vitro generation and ex vivo isolation of apoptotic microvesicles from splenocytes and plasma of MRL/lpr lupus mice and BALB/c control mice.
- Flow cytometry analysis of microvesicles.
- Incubation of bone marrow-derived dendritic cells (BM-DCs) with microvesicles, measuring CD40 expression and cytokine production.
Main Results:
- Microvesicles from MRL/lpr mice exhibited higher levels of modified chromatin compared to BALB/c mice.
- These microvesicles enhanced DC activation and subsequent splenocyte activation.
- Higher interleukin-6 (IL-6) and tumor growth factor-β (TGF-β) production by activated MRL/lpr DCs was observed.
Conclusions:
- Apoptotic microvesicles from MRL/lpr mice are more potent DC activators.
- Dendritic cells from MRL/lpr mice show increased sensitivity to activation by these microvesicles.
- Aberrations in apoptotic microvesicles and DCs likely contribute to the autoimmune response against chromatin in MRL/lpr mice.
