title: Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.
abstract: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1.
  
  
  
  We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP).
  
  
  
  Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1.
  
  
  
  NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwerd
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Yang
authors.affiliation: Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bagola
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jameson
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jung
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Lachmann
authors.affiliation: Great Ormond Street Hospital, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
authors.affiliation: NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Smita Y
authors.initials: SY
authors.lastname: Patel
authors.affiliation: Department of Clinical Immunology, Great Ormond Street Hospital, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Booth
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.affiliation: University Children's Hospital Bonn, Bonn, Germany.
authors.forename: Gesche
authors.initials: G
authors.lastname: Düker
authors.affiliation: Children's Hospital Münster, Münster, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bettels
authors.affiliation: Children's Research Centre Zurich, University Children's Hospital, Zurich, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.affiliation: Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
authors.forename: Satish
authors.initials: S
authors.lastname: Keshav
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Elkadri
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Platt
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alexio M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Children's Hospital Münster, Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.|Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Wraith
authors.affiliation: Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
authors.forename: Mads
authors.initials: M
authors.lastname: Gyrd-Hansen
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK.|Department of Pediatrics, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D001419:Bacteria; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002746:Chlorpromazine / Q000494:pharmacology; D003424:Crohn Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D005839:Gentamicins / Q000494:pharmacology; D006099:Granuloma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear; D008247:Lysosomes; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009154:Mutation; D052556:Niemann-Pick Disease, Type C / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D018492:Dopamine Antagonists; D005839:Gentamicins; D007093:Imidazoles; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C545373:ponatinib; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D002746:Chlorpromazine
keywords: CROHN'S DISEASE; IBD - GENETICS; IBD BASIC RESEARCH; IBD CLINICAL; IMMUNODEFICIENCY