Journal article
Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 6.3MB, Terms of use)
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- Publisher copy:
- 10.1136/gutjnl-2015-310382
Authors
- Funding agency for:
- Gyrd-Hansen, M
- Uhlig, HH
- Grant:
- 102894/Z/13/Z
- Funding agency for:
- Gyrd-Hansen, M
- Grant:
- 102894/Z/13/Z
- Funding agency for:
- Schwerd, T
- Grant:
- SCHW1730/1-1
- Funding agency for:
- Gyrd-Hansen, M
- Grant:
- 102894/Z/13/Z
- Funder identifier:
- https://ror.org/03tx8dq56
- Funding agency for:
- Pandey, S
- Publisher:
- BMJ Publishing Group
- Journal:
- Gut More from this journal
- Volume:
- 66
- Issue:
- 6
- Pages:
- 1060-1073
- Publication date:
- 2016-03-07
- Acceptance date:
- 2016-01-14
- DOI:
- EISSN:
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1468-3288
- ISSN:
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0017-5749
- Language:
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English
- Pubs id:
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pubs:609214
- UUID:
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uuid:068f032d-262e-46b8-bf81-3e023839b419
- Local pid:
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pubs:609214
- Source identifiers:
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609214
- Deposit date:
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2016-03-26
- ARK identifier:
Terms of use
- Copyright holder:
- Schwerd et al
- Copyright date:
- 2016
- Rights statement:
- This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
- Licence:
- CC Attribution (CC BY)
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