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J Allergy Clin Immunol. 2016 May;137(5):1382-1389.e9. doi: 10.1016/j.jaci.2015.09.033. Epub 2015 Nov 14.

Lack of autophagy induces steroid-resistant airway inflammation.

Author information

1
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
2
Johnson & Johnson Pharmaceutical Research and Development, San Diego, Calif.
3
Division of Pulmonary and Critical Care, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
4
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. Electronic address: akbari@usc.edu.

Abstract

BACKGROUND:

Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease.

OBJECTIVE:

We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma.

METHODS:

We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients.

RESULTS:

For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent.

CONCLUSION:

Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

KEYWORDS:

Autophagy; asthma; corticosteroid-resistance asthma; lung inflammation; neutrophilic asthma

Comment in

PMID:
26589586
PMCID:
PMC4860134
DOI:
10.1016/j.jaci.2015.09.033
[Indexed for MEDLINE]
Free PMC Article

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