Faculty Collaboration Database

Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut 2017 Jun;66(6):1060-1073

Date

03/10/2016

Pubmed ID

26953272

Pubmed Central ID

PMC5532464

DOI

10.1136/gutjnl-2015-310382

Scopus ID

2-s2.0-84960874897 (requires institutional sign-in at Scopus site)   114 Citations

Abstract

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.

Author List

Schwerd T, Pandey S, Yang HT, Bagola K, Jameson E, Jung J, Lachmann RH, Shah N, Patel SY, Booth C, Runz H, Düker G, Bettels R, Rohrbach M, Kugathasan S, Chapel H, Keshav S, Elkadri A, Platt N, Muise AM, Koletzko S, Xavier RJ, Marquardt T, Powrie F, Wraith JE, Gyrd-Hansen M, Platt FM, Uhlig HH

Author

Abdul Aziz Elkadri MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylmuramyl-Alanyl-Isoglutamine
Adolescent
Adult
Anti-Bacterial Agents
Autophagy
Bacteria
Cells, Cultured
Child
Child, Preschool
Chlorpromazine
Crohn Disease
Dopamine Antagonists
Female
Genetic Diseases, X-Linked
Gentamicins
Granuloma
Humans
Imidazoles
Leukocytes, Mononuclear
Lysosomes
Macrophages
Male
Mutation
Niemann-Pick Disease, Type C
Nod2 Signaling Adaptor Protein
Protein Kinase Inhibitors
Pyridazines
Receptor-Interacting Protein Serine-Threonine Kinase 2
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
Young Adult