Please use this identifier to cite or link to this item: https://ir.swu.ac.th/jspui/handle/123456789/13923
Title: Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation
Authors: Loison F.
Zhu H.
Karatepe K.
Kasorn A.
Liu P.
Ye K.
Zhou J.
Cao S.
Gong H.
Jenne D.E.
Remold-O'Donnell E.
Xu Y.
Luo H.R.
Keywords: caspase 3
caspase 8
caspase 9
myeloblastin
procaspase 3
proteinase inhibitor
serpinb1 protein
unclassified drug
caspase 3
caspase 8
caspase 9
myeloblastin
superoxide
adoptive transfer
animal cell
animal experiment
apoptosis
Article
cell aging
cell granule
cell maturation
cell survival
controlled study
cytosol
enzyme active site
human
human cell
in vitro study
inflammation
lysosome membrane
membrane permeability
microenvironment
mouse
neutrophil
nonhuman
peritonitis
protein cleavage
signal transduction
animal
apoptosis
bone marrow cell
C57BL mouse
cell separation
cytology
disease model
enzyme activation
flow cytometry
lysosome
metabolism
neutrophil
pathology
transgenic mouse
Animals
Apoptosis
Bone Marrow Cells
Caspase 3
Caspase 8
Caspase 9
Cell Separation
Disease Models, Animal
Enzyme Activation
Flow Cytometry
Humans
Inflammation
Lysosomes
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myeloblastin
Neutrophils
Peritonitis
Superoxides
Issue Date: 2014
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.
URI: https://ir.swu.ac.th/jspui/handle/123456789/13923
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84907494620&doi=10.1172%2fJCI76246&partnerID=40&md5=6174ff3a1bd90cece843065d1ad04846
ISSN: 219738
Appears in Collections:Scopus 1983-2021

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