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FASEB J. 2018 Jun;32(6):3385-3397. doi: 10.1096/fj.201701145R. Epub 2018 Jan 22.

Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases.

Author information

1
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
2
School of Medicine, Cardiff University School of Medicine, Cardiff, United Kingdom.
3
Children's Hospital for Wales, Cardiff, United Kingdom.
4
School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
5
Centre for Medical Education, Cardiff University School of Medicine, Cardiff, United Kingdom.

Abstract

Patients with cystic fibrosis (CF) experience chronic or recurrent bacterial and fungal lung infections. Many patients with CF cannot effectively clear Aspergillus from their lungs. This may result in IgE sensitization and the development of allergic bronchopulmonary aspergillosis, or invasive infections, such as Aspergillus bronchitis. Lung disease in patients with CF is associated with neutrophil-dominated inflammation and elevated levels of the serine protease, neutrophil elastase (NE). Various C-type lectin-like receptors (CLRs), including Dectin-1 and Dectin-2, are involved in the immune response to Aspergillus. Here, we show that purified NE cleaves Dectin-1 in an isoform-specific manner. Bronchoalveolar lavage fluid from patients with CF, which contains high NE activity, induces Dectin-1 cleavage. Similarly, filtrate from a protease-producing strain of Aspergillus fumigatus induces isoform-specific cleavage of Dectin-1. Dectin-1 knockout (KO) cells and NE-treated cells demonstrated reduced phagocytosis of zymosan, a fungal cell wall preparation. In addition, NE cleaves 2 other CLRs, Dectin-2 and Mincle, and fungal-induced cytokine production was reduced in Dectin-1 KO cells, Dectin-2 KO cells, and NE-treated cells. Thus, Dectin-1 and Dectin-2 cleavage by NE and/or A. fumigatus-derived proteases results in an aberrant antifungal immune response that likely contributes to disease pathology in patients with CF.-Griffiths, J. S., Thompson, A., Stott, M., Benny, A., Lewis, N. A., Taylor, P. R., Forton, J., Herrick, S., Orr, S. J., McGreal, E. P. Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases.

KEYWORDS:

Aspergillus; C-type lectin-like receptor; cystic fibrosis; elastase

PMID:
29401615
PMCID:
PMC5956239
DOI:
10.1096/fj.201701145R
[Indexed for MEDLINE]
Free PMC Article

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