Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency

Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2015-06, Vol.194 (11), p.5407-5416
Main Authors: Abdel Fattah, Elmoataz, Bhattacharya, Abhisek, Herron, Alan, Safdar, Zeenat, Eissa, N Tony
Format: Article
Language:English
Subjects:
Animals
Autophagy - immunology
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Bleomycin - pharmacology
Bronchoalveolar Lavage Fluid - immunology
Collagen - metabolism
Cytokines - blood
Cytokines - metabolism
Fibrosis - genetics
Fibrosis - immunology
Goblet Cells - immunology
Inflammasomes - immunology
Interleukin-18 - genetics
Interleukin-18 - immunology
Lipopolysaccharides - administration & dosage
Lung - immunology
Lung - pathology
Metaplasia
Mice
Mice, Inbred C57BL
Mice, Knockout
Microtubule-Associated Proteins - genetics
Pneumonia - immunology
Pneumonia - mortality
Pneumonia - pathology
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Summary:Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia, and increased collagen content. Lung inflammation was associated with increase in several proinflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by IL-18 as a result of constitutive inflammasome activation. Following i.p. LPS injection, autophagy-deficient mice had higher levels of proinflammatory cytokines in lungs and in serum, as well as increased mortality, than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy-deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1402277