title: Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation.
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 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.
authors.forename: Fabien
authors.initials: F
authors.lastname: Loison
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhu
authors.forename: Kutay
authors.initials: K
authors.lastname: Karatepe
authors.forename: Anongnard
authors.initials: A
authors.lastname: Kasorn
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Zhou
authors.forename: Shannan
authors.initials: S
authors.lastname: Cao
authors.forename: Haiyan
authors.initials: H
authors.lastname: Gong
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
authors.forename: Yuanfu
authors.initials: Y
authors.lastname: Xu
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002469:Cell Separation; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053146:Myeloblastin / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010538:Peritonitis / Q000378:metabolism; D013481:Superoxides
chemical_list: D013481:Superoxides; D053146:Myeloblastin; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9