TY - JOUR

T1 - Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

AU - Schwerd, Tobias

AU - Pandey, Sumeet

AU - Yang, Huei-Ting

AU - Bagola, Katrin

AU - Jameson, Elisabeth

AU - Jung, Jonathan

AU - Lachmann, Robin H

AU - Shah, Neil

AU - Patel, Smita Y

AU - Booth, Claire

AU - Runz, Heiko

AU - Düker, Gesche

AU - Bettels, Ruth

AU - Rohrbach, Marianne

AU - Kugathasan, Subra

AU - Chapel, Helen

AU - Keshav, Satish

AU - Elkadri, Abdul

AU - Platt, Nick

AU - Muise, Alexio M

AU - Koletzko, Sibylle

AU - Xavier, Ramnik J

AU - Marquardt, Thorsten

AU - Powrie, Fiona

AU - Wraith, James E

AU - Gyrd-Hansen, Mads

AU - Platt, Frances M

AU - Uhlig, Holm H

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/6

Y1 - 2017/6

N2 - OBJECTIVE: 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.DESIGN: 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).RESULTS: 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.CONCLUSIONS: 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.

AB - OBJECTIVE: 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.DESIGN: 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).RESULTS: 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.CONCLUSIONS: 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.

KW - Acetylmuramyl-Alanyl-Isoglutamine/metabolism

KW - Adolescent

KW - Adult

KW - Anti-Bacterial Agents/pharmacology

KW - Autophagy/drug effects

KW - Bacteria

KW - Cells, Cultured

KW - Child

KW - Child, Preschool

KW - Chlorpromazine/pharmacology

KW - Crohn Disease/complications

KW - Dopamine Antagonists/pharmacology

KW - Female

KW - Genetic Diseases, X-Linked/genetics

KW - Gentamicins/pharmacology

KW - Granuloma/genetics

KW - Humans

KW - Imidazoles/pharmacology

KW - Leukocytes, Mononuclear

KW - Lysosomes

KW - Macrophages/drug effects

KW - Male

KW - Mutation

KW - Niemann-Pick Disease, Type C/complications

KW - Nod2 Signaling Adaptor Protein/genetics

KW - Protein Kinase Inhibitors/pharmacology

KW - Pyridazines/pharmacology

KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors

KW - Tumor Necrosis Factor-alpha/metabolism

KW - X-Linked Inhibitor of Apoptosis Protein/deficiency

KW - Young Adult

U2 - 10.1136/gutjnl-2015-310382

DO - 10.1136/gutjnl-2015-310382

M3 - Journal article

C2 - 26953272

VL - 66

SP - 1060

EP - 1073

JO - Gut

JF - Gut

SN - 0017-5749

IS - 6

ER -