Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1

Burgener, Sabrina; Baumann, Mathias; Basilico, Paola; Remold-O'Donnell, Eileen; Touw, Ivo P; Benarafa, Charaf (2016). Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1. Biological chemistry, 397(9), pp. 897-905. De Gruyter 10.1515/hsz-2016-0132

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Serpinb1 is an inhibitor of neutrophil granule serine proteases cathepsin G, proteinase-3 and elastase. One of its core physiological functions is to protect neutrophils from granule protease-mediated cell death. Mice lacking Serpinb1a (Sb1a-/-), its mouse ortholog, have reduced bone marrow neutrophil numbers due to cell death mediated by cathepsin G and the mice show increased susceptibility to lung infections. Here, we show that conditional deletion of Serpinb1a using the Lyz2-cre and Cebpa-cre knock-in mice effectively leads to recombination-mediated deletion in neutrophils but protein-null neutrophils were only obtained using the latter recombinase-expressing strain. Absence of Serpinb1a protein in neutrophils caused neutropenia and increased granule permeabilization-induced cell death. We then generated transgenic mice expressing human Serpinb1 in neutrophils under the human MRP8 (S100A8) promoter. Serpinb1a expression levels in founder lines correlated positively with increased neutrophil survival when crossed with Sb1a-/- mice, which had their defective neutrophil phenotype rescued in the higher expressing transgenic line. Using new conditional and transgenic mouse models, our study demonstrates the presence of a relatively low Serpinb1a protein threshold in neutrophils that is required for sustained survival.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Burgener, Sabrina; Baumann, Mathias; Basilico, Paola and Benarafa, Charaf

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1431-6730

Publisher:

De Gruyter

Funders:

[4] Swiss National Science Foundation
[UNSPECIFIED] Marie Curie International Reintegration Grant
[UNSPECIFIED] Bern University Research Foundation
[UNSPECIFIED] National Institutes of Health

Language:

English

Submitter:

Sabrina Burgener

Date Deposited:

22 May 2017 14:38

Last Modified:

22 May 2017 14:38

Publisher DOI:

10.1515/hsz-2016-0132

PubMed ID:

27107834

BORIS DOI:

10.7892/boris.97611

URI:

https://boris.unibe.ch/id/eprint/97611

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