title: Deficient autophagy unravels the ROS paradox in chronic granulomatous disease.
abstract: Autophagy defects resulting in inflammation appear to be a key feature in the pathogenesis of Crohn colitis. An inflammatory colitis indistinguishable from Crohn disease is described in patients with chronic granulomatous disease (CGD). Patients with CGD have a mutated NADPH complex and are therefore deficient in reactive oxygen species (ROS) production; however, the underlying mechanism for the inflammatory colitis in CGD remained unknown. In a recent study, our group reported that NADPH-dependent ROS deficiency results in autophagic dysfunction that subsequently contributes to increased IL1B/interleukin 1β production. Mice deficient in the NADPH-complex component NCF4/p40phox, and CGD patients with a defect in NCF4 display minimal recruitment of LC3 to phagosomes in response to internalized bacteria and fungi. Human monocytes from patients with CGD with defective LC3 recruitment show increased IL1B production after LPS stimulation. Blocking IL1 protects NCF4-deficient mice from experimental colitis; importantly, improved clinical outcome in 2 CGD patients with colitis is also observed with IL1 blockade. Moreover, blocking IL1 restores defective autophagy in CGD mice and cells from patients with CGD. Thus, autophagic dysfunction underlies the pathogenesis of granulomatous colitis in CGD, and blocking IL1 can be used to treat CGD colitis.
authors.affiliation: Department of Medicine; Radboud University Nijmegen Medical Centre; Nijmegen, The Netherlands; University of Colorado; Denver, CO USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Medicine; Radboud University Nijmegen Medical Centre; Nijmegen, The Netherlands; University of Colorado; Denver, CO USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003092:Colitis / Q000188:drug therapy*; D006105:Granulomatous Disease, Chronic / Q000188:drug therapy*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D010588:Phagosomes / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1
keywords: CGD; Crohn disease; LC3-associated phagocytosis; aspergillosis; colitis; inflammation; interleukin-1