IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans

de Luca, Antonella, Smeekens, Sanne P., Casagrande, Andrea, Iannitti, Rossana, Conway, Kara L., Gresnigt, Mark. S., Begun, Jakob, Plantinga, Theo S., Joosten, Leo A. B., van der Meer, Jos W. M., Chamilos, Georgios, Netea, Mihai G., Xavier, Ramnik J., Dinarello, Charles A., Romani, Luigina and van de Veerdonk, Frank L. (2014) IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proceedings of the National Academy of Sciences of the United States of America, 111 9: 3526-3531. doi:10.1073/pnas.1322831111


Author de Luca, Antonella
Smeekens, Sanne P.
Casagrande, Andrea
Iannitti, Rossana
Conway, Kara L.
Gresnigt, Mark. S.
Begun, Jakob
Plantinga, Theo S.
Joosten, Leo A. B.
van der Meer, Jos W. M.
Chamilos, Georgios
Netea, Mihai G.
Xavier, Ramnik J.
Dinarello, Charles A.
Romani, Luigina
van de Veerdonk, Frank L.
Title IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2014-03-04
Sub-type Article (original research)
DOI 10.1073/pnas.1322831111
Open Access Status DOI
Volume 111
Issue 9
Start page 3526
End page 3531
Total pages 6
Place of publication Washington DC United States
Publisher National Academy of Sciences
Language eng
Formatted 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.
Keyword Autoinflammatory disease
Crohn disease
Interleukin-1
LPS
S. aureus
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Non HERDC
 
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Created: Wed, 24 Sep 2014, 19:57:26 EST by Ms Kate Rowe on behalf of Mater McAuley Library