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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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