Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (9), p.3526-3531
2014
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- Autor(en) / Beteiligte
- Titel
- IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (9), p.3526-3531
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2014
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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 oxidasedeficient 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1322831111Titel-ID: cdi_proquest_miscellaneous_1504739836
- Format
- –
- Schlagworte
- Animals, Antagonist drugs, Anti-Inflammatory Agents - pharmacology, Anti-Inflammatory Agents - therapeutic use, Aspergillus, Aspergillus fumigatus, Autophagy, Autophagy - physiology, Biological Sciences, Chronic granulomatous disease, Chronic illnesses, Colitis, Colitis - drug therapy, Colitis - etiology, Colitis - immunology, Crohn disease, Enzyme-Linked Immunosorbent Assay, Gene expression, Granulomatous Disease, Chronic - complications, Granulomatous Disease, Chronic - drug therapy, Granulomatous Disease, Chronic - immunology, Humans, Infections, Inflammation, Inflammatory diseases, Interleukin 1 Receptor Antagonist Protein - pharmacology, Interleukin 1 Receptor Antagonist Protein - therapeutic use, Interleukin-1beta - metabolism, Lungs, Macrophages, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microtubule-Associated Proteins - metabolism, Monocytes, NADPH Oxidases - deficiency, NADPH Oxidases - genetics, Phagosomes - metabolism, Proteins, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-1 - antagonists & inhibitors, Rodents, Statistics, Nonparametric