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Title: Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation
Authors: Fabien Loison
Haiyan Zhu
Kutay Karatepe
Anongnard Kasorn
Peng Liu
Keqiang Ye
Jiaxi Zhou
Shannan Cao
Haiyan Gong
Dieter E. Jenne
Eileen Remold-O'Donnell
Yuanfu Xu
Hongbo R. Luo
Children's Hospital Boston
Mahidol University
Institute of Hematology and Blood Disease Hospital
Srinakharinwirot University
Emory University
Helmholtz Center Munich German Research Center for Environmental Health
Keywords: Medicine
Issue Date: 1-Jan-2014
Citation: Journal of Clinical Investigation. Vol.124, No.10 (2014), 4445-4458
Abstract: 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 infammation 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.
ISSN: 15588238
Appears in Collections:Scopus 2011-2015

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