Publication:
Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation

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Issued Date

2014

Resource Type

Article

File Type

application/pdf

ISSN

219738

DOI

10.1172/JCI76246

Other identifier(s)

2-s2.0-84907494620

Rights Holder(s)

Scopus

Bibliographic Citation

Journal of Clinical Investigation. Vol 124, No.10 (2014), p.4445-4458

Suggested Citation

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. Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. Journal of Clinical Investigation. Vol 124, No.10 (2014), p.4445-4458. doi:10.1172/JCI76246 Retrieved from: https://hdl.handle.net/20.500.14740/6448

Title

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

Author(s)

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.

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.

Subject(s)

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

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URI

https://hdl.handle.net/20.500.14740/6448

Collections

Scopus: Year 1983-2021

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