Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease.
Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox. We report that mononuclear phagocytes from CGD patients activated caspase-1 and produced biologically active interleukin-1beta (IL-1beta) in response to danger signals. Notably, caspase-1 activation and IL-1beta secretion from CGD monocytes was elevated in asymptomatic patients and strongly increased in patients with noninfectious inflammatory conditions. Treatment with IL-1 receptor antagonist reduced IL-1 production in monocytes ex vivo and during medical therapy. Our results identify phagocyte oxidase defective monocytes as a source of elevated IL-1 and provide a potential therapeutic option to ameliorate inflammatory conditions associated with CGD.
Meissner
Felix
F
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
Seger
Reinhard A
RA
Moshous
Despina
D
Fischer
Alain
A
Reichenbach
Janine
J
Zychlinsky
Arturo
A
D018501:Antirheumatic Agents / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency*; D010586:Phagocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D020170:Caspase 1