title: IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans.
abstract: Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: de Luca
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: Andrea
authors.initials: A
authors.lastname: Casagrande
authors.forename: Rossana
authors.initials: R
authors.lastname: Iannitti
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.forename: Jakob
authors.initials: J
authors.lastname: Begun
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001232:Aspergillus fumigatus; D001343:Autophagy / Q000502:physiology; D003092:Colitis / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D010588:Phagosomes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D018709:Statistics, Nonparametric
chemical_list: D000893:Anti-Inflammatory Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D017472:Receptors, Interleukin-1; D019255:NADPH Oxidases
keywords: Crohn disease; LPS; S. aureus; autoinflammatory disease; interleukin-1