IL-1R1/MyD88 signaling is critical for elastase-induced lung inflammation and emphysema.
Lung emphysema and fibrosis are severe complications of chronic obstructive pulmonary disease, and uncontrolled protease activation may be involved in the pathogenesis. Using experimental elastase-induced acute inflammation, we demonstrate here that inflammation and development of emphysema is IL-1R1 and Toll/IL-1R signal transduction adaptor MyD88 dependent; however, TLR recognition is dispensable in this model. Elastase induces IL-1beta, TNF-alpha, keratinocyte-derived chemokine, and IL-6 secretion and neutrophil recruitment in the lung, which is drastically reduced in the absence of IL-1R1 or MyD88. Further, tissue destruction with emphysema and fibrosis is attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Specific blockade of IL-1 by IL-1R antagonist diminishes acute inflammation and emphysema. Finally, IL-1beta production and inflammation are reduced in mice deficient for the NALP3 inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and we identified uric acid, which is produced upon elastase-induced lung injury, as an activator of the NALP3/ASC inflammasome. In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1beta production. IL-1beta therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema.
Couillin
Isabelle
I
Laboratory of Molecular Immunology and Embryology, University of Orleans and Centre National de la Recherche Scientifique, Orleans, France. couillin@cnrs-orleans.fr
Vasseur
Virginie
V
Charron
Sabine
S
Gasse
Pamela
P
Tavernier
Marie
M
Guillet
Julien
J
Lagente
Vincent
V
Fick
Lizette
L
Jacobs
Muazzam
M
Coelho
Fernando Rodrigues
FR
Moser
René
R
Ryffel
Bernhard
B
D000818:Animals; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology* / Q000633:toxicity; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D010196:Pancreatic Elastase / Q000008:administration & dosage / Q000633:toxicity*; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D053573:Receptors, Interleukin-1 Type I / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013552:Swine; D051193:Toll-Like Receptors / Q000502:physiology
D018836:Inflammation Mediators; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D051193:Toll-Like Receptors; D010196:Pancreatic Elastase