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Loison, F.* ; Zhu, H.* ; Karatepe, K.* ; Kasorn, A.* ; Liu, P.* ; Ye, K.* ; Zhou, J.* ; Cao, S.* ; Gong, H.* ; Jenne, D. ; Remold-O'Donnell, E.* ; Xu, Y.* ; Luo, H.R.*

Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation.

J. Clin. Invest. 124, 4445-4458 (2014)
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Caspase-3-mediated spontaneous death in neutrophils is a prototype of programmed cell death and is critical for modulating physiopathological inflammatory responses; however, the underlying regulatory pathways remain ill defined. Here we determined that in aging neutrophils, the cleavage and activation of caspase-3 is independent of the canonical caspase-8- or caspase-9-mediated pathway. Instead, caspase-3 activation was mediated by serine protease proteinase 3 (PR3), which is present in the cytosol of aging neutrophils. Specifically, PR3 cleaved procaspase-3 at a site upstream of the canonical caspase-9 cleavage site. In mature neutrophils, PR3 was sequestered in granules and released during aging via lysosomal membrane permeabilization (LMP), leading to procaspase-3 cleavage and apoptosis. Pharmacological inhibition or knockdown of PR3 delayed neutrophil death in vitro and consistently delayed neutrophil death and augmented neutrophil accumulation at sites of inflammation in a murine model of peritonitis. Adoptive transfer of both WT and PR3-deficient neutrophils revealed that the delayed death of neutrophils lacking PR3 is due to an altered intrinsic apoptosis/survival pathway, rather than the inflammatory microenvironment. The presence of the suicide protease inhibitor SERPINB1 counterbalanced the protease activity of PR3 in aging neutrophils, and deletion of Serpinb1 accelerated neutrophil death. Taken together, our results reveal that PR3-mediated caspase-3 activation controls neutrophil spontaneous death.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cell-death; Serine Proteases; Polymorphonuclear Leukocytes; Cathepsin-g; Apoptosis; Activation; Mechanisms; Elastase; Granules; Serpinb1
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 124, Issue: 10, Pages: 4445-4458 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place Ann Arbor
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)