Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1
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Sabrina S. Burgener
, Mathias Baumann , Paola Basilico , Eileen Remold-O’Donnell , Ivo P. Touw and Charaf Benarafa
Abstract
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. These models will also be helpful in delineating recently described functions of Serpinb1 in metabolism and cancer.
Acknowledgments
We thank Elisabeth Frei and Stephan Hirschi for excellent technical assistance. We acknowledge Albert Witt for pronucleus microinjection, Lina Du for ES cell injection and Bernadette Nyfeler for cell sorting. We thank the ZEMB and DKF animal caretaker teams for dedicated attention and husbandry. This study was supported by grants from the Swiss National Science Foundation (127464 and 149790) (CB), the EU/FP7 Marie Curie International Reintegration Grant (CB) grant 249297 and the Bern University Research Foundation (CB). Serpinb1a+/F mice were generated with support from the National Institutes of Health grant HL66548 (ERO).
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The online version of this article (DOI: 10.1515/hsz-2016-0132) offers supplementary material, available to authorized users.
©2016 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: proteolytic networks across cellular boundaries
- HIGHLIGHT: IPS 2015 – 9TH GENERAL MEETING OF THE INTERNATIONAL PROTEOLYSIS SOCIETY
- A personal journey with matrix metalloproteinases
- Type II transmembrane serine proteases as potential targets for cancer therapy
- Membrane trafficking and proteolytic activity of γ-secretase in Alzheimer’s disease
- Dipeptidyl peptidase 9 substrates and their discovery: current progress and the application of mass spectrometry-based approaches
- Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains
- Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors
- Granzyme B inhibits keratinocyte migration by disrupting epidermal growth factor receptor (EGFR)-mediated signaling
- Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1
- Probing catalytic rate enhancement during intramembrane proteolysis
- Human 20S proteasome activity towards fluorogenic peptides of various chain lengths
- Research Articles/Short Communications
- Protein Structure and Function
- Biophysical analysis of three novel profilin-1 variants associated with amyotrophic lateral sclerosis indicates a correlation between their aggregation propensity and the structural features of their globular state
- The potential of the Galleria mellonella innate immune system is maximized by the co-presentation of diverse antimicrobial peptides