SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

Baumann, Mathias; Pham, Christine T. N.; Benarafa, Charaf (2013). SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G. Blood, 121(19), pp. 3900-3907. The American Society of Hematology 10.1182/blood-2012-09-455022

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Bone marrow (BM) holds a large reserve of polymorphonuclear neutrophils (PMNs) that are rapidly mobilized to the circulation and tissues in response to danger signals. SerpinB1 is a potent inhibitor of neutrophil serine proteases neutrophil elastase (NE) and cathepsin G (CG). SerpinB1 deficiency (sB1(-/-)) results in a severe reduction of the BM PMN reserve and failure to clear bacterial infection. Using BM chimera, we found that serpinB1 deficiency in BM cells was necessary and sufficient to reproduce the BM neutropenia of sB1(-/-) mice. Moreover, we showed that genetic deletion of CG, but not NE, fully rescued the BM neutropenia in sB1(-/-) mice. In mixed BM chimera and in vitro survival studies, we showed that CG modulates sB1(-/-) PMN survival through a cell-intrinsic pathway. In addition, membrane permeabilization by lysosomotropic agent l-leucyl-l-leucine methyl ester that allows cytosolic release of granule contents was sufficient to induce rapid PMN death through a CG-dependent pathway. CG-mediated PMN cytotoxicity was only partly blocked by caspase inhibition, suggesting that CG cleaves a distinct set of targets during apoptosis. In conclusion, we have unveiled a new cytotoxic function for the serine protease CG and showed that serpinB1 is critical for maintaining PMN survival by antagonizing intracellular CG activity.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Baumann, Mathias and Benarafa, Charaf

Subjects:

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

ISSN:

0006-4971

Publisher:

The American Society of Hematology

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

12 Jun 2014 15:07

Last Modified:

02 Dec 2015 13:17

Publisher DOI:

10.1182/blood-2012-09-455022

PubMed ID:

23532733

BORIS DOI:

10.7892/boris.46474

URI:

https://boris.unibe.ch/id/eprint/46474

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