Article Text

A1.23 Macroautophagy deficiency in dendritic cells exacerbates antigen-induced arthritis
  1. J Niven1,2,
  2. G Palmer-Lourenco1,2,
  3. D Talabot-Ayer1,2,
  4. C Gabay1,2,
  5. M Gannagé1,2
  1. 1Division of Rheumatology, School of Medicine, Rue Michel Servet 1, University of Geneva 1211 Geneva 4, Switzerland
  2. 2Department of Pathology and Immunology, School of Medicine, Rue Michel Servet 1, University of Geneva 1211 Geneva 4, Switzerland


Background and objectives Macroautophagy is a major catabolic pathway in cells, acting in parallel to the proteasome machinery. This pathway is an important contributor of cellular homeostasis, and therefore is active and up regulated in various conditions of cellular stress and inflammation. In this context, macroautophagy has been implicated in shaping the innate and adaptive immune responses by acting at multiple and diverse levels including cytokine secretion and antigen presentation. Our aim was to analyse the contribution of macroautophagy in the immune response during autoimmune arthritis, using mice that are deficient in autophagy in their dendritic cells.

Materials and methods Mice: CD11c-Cre mice (C57BL/6), (Jackson Laboratory) were crossed with Atg5flox/floxmice (C57BL/6) provided by Dr. Noboru Mizushima (Japan). Since ATG5 is an essential autophagy gene, its targeted deletion in dendritic cells completely abolished a functional autophagy pathway in these cells.

For the Antigen induced arthritis mice model, mice were immunised with methylated BSA (mBSA) and CFA, with a boost at day 7. Monoarthritis was induced at day 21 by injection of mBSA into the knee joint. Animals were sacrificed at day 28. Sections from knees were stained with hematoxylin and eosin and macroscopic scoring of the cellular infiltrate was performed. In parallel, toluidine blue staining was used for cartilage damage scoring. ELISA was used to determine the antibody titers against mBSA. T cell function was monitored by cytokine production, after in vitro re-stimulation with mBSA, using single cell suspensions from lymph nodes and spleens. mRNA levels of inflammatory cytokines were measured by quantitative PCR, after RNA extraction from the immunised hind limbs.

Results We found enhanced cartilage destruction in mice lacking autophagy in their dendritic cells (DC/ATG5-/-). Interestingly, the TH1/TH17 response in DC/ATG5-/- mice was significantly increased. Indeed, T cells derived from spleens and lymph nodes of DC/ATG5-/- mice and their wild type littermate controls (DC/ATG5 +/+) were cultured in vitro for 48 h, with mBSA or CD3/CD28. A significant increase in INF-gamma and IL-17 production was assessed in T cell cultures from DC/ATG5-/- mice. In parallel, in vivo, pro-inflammatory cytokines production was locally enhanced since IL-1 beta, IL-23, and IL-17 transcripts levels were significantly higher in DC/ATG5-/- mice compare to their littermate controls.

Conclusions Autophagy deficiency in dendritic cells enhances the TH1/TH17 inflammatory response in the AIA model, resulting in increased cartilage destruction. The precise mechanism behind this regulation is under investigation.

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