Efferocytosis Promotes Suppressive Effects on Dendritic Cells through Prostaglandin E2 Production in the Context of Autoimmunity

Irma Pujol-Autonell,
Rosa-Maria Ampudia,
Raquel Planas,
Silvia Marin-Gallen,
Jorge Carrascal,
Alex Sanchez,
Ana Marin,
Manuel Puig-Domingo,
Ricardo Pujol-Borrell,
Joan Verdaguer,
Marta Vives-Pi mail

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Abstract

Introduction

Efferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, may be restored by the administration of autologous dendritic cells loaded with islet apoptotic cells in experimental type 1 diabetes.

Objective

To evaluate tolerogenic properties in dendritic cells induced by the clearance of apoptotic islet cells, thus explaining the re-establishment of tolerance in a context of autoimmunity.

Methods

Bone marrow derived dendritic cells from non-obese diabetic mice, a model of autoimmune diabetes, were generated and pulsed with islet apoptotic cells. The ability of these cells to induce autologous T cell proliferation and to suppress mature dendritic cell function was assessed, together with cytokine production. Microarray experiments were performed using dendritic cells to identify differentially expressed genes after efferocytosis.

Results

Molecular and functional changes in dendritic cells after the capture of apoptotic cells were observed. 1) Impaired ability of dendritic cells to stimulate autologous T cell proliferation after the capture of apoptotic cells even after proinflammatory stimuli, with a cytokine profile typical for immature dendritic cells. 2) Suppressive ability of mature dendritic cell function. 3) Microarray-based gene expression profiling of dendritic cells showed differential expression of genes involved in antigen processing and presentation after efferocytosis. 4) Prostaglandin E2 increased production was responsible for immunosuppressive mechanism of dendritic cells after the capture of apoptotic cells.

Conclusions

The tolerogenic behaviour of dendritic cells after islet cells efferocytosis points to a mechanism of silencing potential autoreactive T cells in the microenvironment of autoimmunity. Our results suggest that dendritic cells may be programmed to induce specific immune tolerance using apoptotic cells; this is a viable strategy for a variety of autoimmune diseases.

Citation: Pujol-Autonell I, Ampudia R-M, Planas R, Marin-Gallen S, Carrascal J, et al. (2013) Efferocytosis Promotes Suppressive Effects on Dendritic Cells through Prostaglandin E2 Production in the Context of Autoimmunity. PLoS ONE 8(5): e63296. doi:10.1371/journal.pone.0063296
Editor: Massimo Pietropaolo, University of Michigan Medical School, United States of America
Received: December 11, 2012; Accepted: April 2, 2013; Published: May 15, 2013
Copyright: © 2013 Pujol-Autonell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the Fondo de Investigaciones Sanitarias (PS09/00253 and PI12/00195) of the Carlos III Institute of Health, www.isciii.es. RP was supported by the Instituto de Salud Carlos III of the Spanish National Institute of Health (FIS05/00418). MVP is funded by the stabilization program of Miguel Servet biomedical researchers and RMA by the program of research technicians of the Instituto de Salud Carlos III and Direcció d’Estrategia i Coordinacio, Health Dept. of the Catalonian Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.