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NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Nature Medicine volume 16, pages 90–97 (2010)Cite this article

Abstract

Nucleotide-binding oligomerization domain–containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4+ T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease—associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease–associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.

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Figure 1: Muramyldipeptide (MDP) induces autophagy in DCs.
Figure 2: NOD2 signaling is required for MDP-Induced autophagy.
Figure 3: MDP-induced autophagy requires PI3K, ATG5, ATG7 and ATG16L1.
Figure 4: NOD2-mediated autophagosome formation is required for MDP-mediated MHC class II upregulation and antigen presentation.
Figure 5: Failure in NOD2-mediated autophagy induction and antigen presentation in DCs expressing Crohn's disease–associated NOD2 and ATG16L1 variants.
Figure 6: Crohn's disease–variant NOD2 is associated with aberrant bacterial handling in DCs.

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Acknowledgements

We would like to acknowledge the previous researchers in our department involved in genotyping of the Oxford Crohn's disease cohort and thank A.-K. Simon and A. McMichael for helpful discussions. Most particularly, we would like to thank all of our donors who generously gave blood samples for this study. We are supported by grants from the UK Medical Research Council (J.B., T.P. and A.S.), the UK Higher Education Funding Council (A.S.), Oxford National Institute for Health Research Biomedical Research Centre (A.S.) and the National Institute of Health Research Specialist Biomedical Research Centre in Microbial Disease (01CD1) (B.J.C.), Action Medical Research (R.C.), Digestive Disorders Foundation and National Association for Crohn's and Colitis and The Barbour Trust in Memory of Simon Ash (O.B.), Fondation Philippe Weiner Maurice Anspach (B.D.) and the Wellcome Trust (P.A.). The GFP-LC3 construct was a kind gift from H. Mellor (University of Oxford) GFP–S. enterica typhimurium was a kind gift from D. Holden (Imperial College, University of London) and SL5338 pTECH1 was a kind gift from K. Turner (Sanger Centre).

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Author notes

  1. Rachel Cooney and John Baker: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Headington, Oxford, UK

    Rachel Cooney, John Baker, Oliver Brain, Benedicte Danis, Tica Pichulik, Philip Allan & Alison Simmons

  2. Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK

    Rachel Cooney, Oliver Brain, Philip Allan, Derek Jewell & Alison Simmons

  3. Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Headington, Oxford, UK

    David J P Ferguson

  4. School of Clinical Sciences, University of Liverpool, Duncan Building, Liverpool, UK

    Barry J Campbell

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  1. Rachel Cooney
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Contributions

A.S. conceived the idea; A.S., J.B. and R.C. designed the experiments and prepared the manuscript; R.C., J.B., O.B., P.A. and A.S. did RNAi, flow cytometry, immunoblot and confocal experiments. J.B., R.C., O.B. and P.A. were involved with gene sequencing of NOD2 and ATG16L1. T.P. and B.D. provided technical assistance and participated in flow cytometry experiments; D.J.P.F. did the electron microscopy analysis; B.J.C. provided GFP–E. coli, and B.J.C. and D.J. provided additional intellectual input.

Corresponding author

Correspondence to Alison Simmons.

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Cooney, R., Baker, J., Brain, O. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16, 90–97 (2010). https://doi.org/10.1038/nm.2069

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