NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.
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.
Cooney
Rachel
R
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Headington, Oxford, UK.
Baker
John
J
Brain
Oliver
O
Danis
Benedicte
B
Pichulik
Tica
T
Allan
Philip
P
Ferguson
David J P
DJ
Campbell
Barry J
BJ
Jewell
Derek
D
Simmons
Alison
A
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D017951:Antigen Presentation / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005802:Genes, MHC Class II / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000502:physiology
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine