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

Abstract

ObjectivePatients 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.DesignWe 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).ResultsPatients 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.ConclusionsNPC1 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.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway

“…This may have significant implications for NPC patients as it suggests they are likely to have altered microbial handling, and as a result harbour an unusual microbiome, and potentially have greater susceptibly to Mtb infection. Indeed, altered microbial handling was recently demonstrated in vitro and linked to a high penetrance of Crohn's disease in NPC1 patients 59 .…”

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

“…Because a failure in the functioning of lysosomes can be induced in various settings, including genetic factors 35, 36 , oxidative stress 37 , and mitochondrial dysfunction 38 , increasing evidence indicates that lysosomal impairment is associated with activation of inflammatory signals 9, 39 . For instance, impairment of the autophagy–lysosome pathway causes dysfunction of mitochondrial clearance, which results in generation of ROS and a release of mitochondrial DNA 9 .…”

Making sense of the cause of Crohn’s – a new look at an old disease

“…CD resulting from abnormal xenophagy is seen in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease 319 . Other proteins implicated in xenophagy are the autophagy receptor CALCOCO2/NDP52 320 , Leucine-rich repeat kinase 2 (LRRK2) 321 and Optineurin 322, 323 .…”