Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.
<h4>Objective</h4> <p>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 bacte...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
BMJ Publishing Group
2016
|
| _version_ | 1826257671102136320 |
|---|---|
| author | Schwerd, T Pandey, S Yang, H Bagola, K Jameson, E Jung, J Lachmann, R Shah, N Patel, S Booth, C Runz, H Düker, G Bettels, R Rohrbach, M Kugathasan, S Chapel, H Keshav, S Elkadri, A Platt, N Muise, A Koletzko, S Xavier, R Marquardt, T Powrie, F Wraith, J Gyrd-Hansen, M Platt, F Uhlig, H |
| author_facet | Schwerd, T Pandey, S Yang, H Bagola, K Jameson, E Jung, J Lachmann, R Shah, N Patel, S Booth, C Runz, H Düker, G Bettels, R Rohrbach, M Kugathasan, S Chapel, H Keshav, S Elkadri, A Platt, N Muise, A Koletzko, S Xavier, R Marquardt, T Powrie, F Wraith, J Gyrd-Hansen, M Platt, F Uhlig, H |
| author_sort | Schwerd, T |
| collection | OXFORD |
| description | <h4>Objective</h4> <p>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.</p> <h4>Design</h4> <p>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).</p> <h4>Results</h4> <p>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-receptorinteracting 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.</p> <h4>Conclusions</h4> <p>NPC1 confers increased risk of earlyonset 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.</p> |
| first_indexed | 2024-03-06T18:21:50Z |
| format | Journal article |
| id | oxford-uuid:068f032d-262e-46b8-bf81-3e023839b419 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:21:50Z |
| publishDate | 2016 |
| publisher | BMJ Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:068f032d-262e-46b8-bf81-3e023839b4192022-03-26T09:03:16ZImpaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:068f032d-262e-46b8-bf81-3e023839b419EnglishSymplectic Elements at OxfordBMJ Publishing Group2016Schwerd, TPandey, SYang, HBagola, KJameson, EJung, JLachmann, RShah, NPatel, SBooth, CRunz, HDüker, GBettels, RRohrbach, MKugathasan, SChapel, HKeshav, SElkadri, APlatt, NMuise, AKoletzko, SXavier, RMarquardt, TPowrie, FWraith, JGyrd-Hansen, MPlatt, FUhlig, H<h4>Objective</h4> <p>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.</p> <h4>Design</h4> <p>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).</p> <h4>Results</h4> <p>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-receptorinteracting 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.</p> <h4>Conclusions</h4> <p>NPC1 confers increased risk of earlyonset 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.</p> |
| spellingShingle | Schwerd, T Pandey, S Yang, H Bagola, K Jameson, E Jung, J Lachmann, R Shah, N Patel, S Booth, C Runz, H Düker, G Bettels, R Rohrbach, M Kugathasan, S Chapel, H Keshav, S Elkadri, A Platt, N Muise, A Koletzko, S Xavier, R Marquardt, T Powrie, F Wraith, J Gyrd-Hansen, M Platt, F Uhlig, H Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title | Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title_full | Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title_fullStr | Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title_full_unstemmed | Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title_short | Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. |
| title_sort | impaired antibacterial autophagy links granulomatous intestinal inflammation in niemann pick disease type c1 and xiap deficiency with nod2 variants in crohn s disease |
| work_keys_str_mv | AT schwerdt impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT pandeys impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT yangh impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT bagolak impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT jamesone impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT jungj impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT lachmannr impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT shahn impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT patels impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT boothc impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT runzh impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT dukerg impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT bettelsr impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT rohrbachm impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT kugathasans impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT chapelh impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT keshavs impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT elkadria impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT plattn impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT muisea impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT koletzkos impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT xavierr impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT marquardtt impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT powrief impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT wraithj impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT gyrdhansenm impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT plattf impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease AT uhligh impairedantibacterialautophagylinksgranulomatousintestinalinflammationinniemannpickdiseasetypec1andxiapdeficiencywithnod2variantsincrohnsdisease |