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.

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