title: Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection.
abstract: Neutrophil elastase (NE) and cathepsin G (CG) contribute to intracellular microbial killing but, if left unchecked and released extracellularly, promote tissue damage. Conversely, mechanisms that constrain neutrophil serine protease activity protect against tissue damage but may have the untoward effect of disabling the microbial killing arsenal. The host elaborates thrombospondin-1 (TSP-1), a matricellular protein released during inflammation, but its role during neutrophil activation following microbial pathogen challenge remains uncertain. Mice deficient in TSP-1 (thbs1(-/-)) showed enhanced lung bacterial clearance, reduced splenic dissemination, and increased survival compared with wild-type (WT) controls during intrapulmonary Klebsiella pneumoniae infection. More effective pathogen containment was associated with reduced burden of inflammation in thbs1(-/-) mouse lungs compared with WT controls. Lung NE activity was increased in thbs1(-/-) mice following K. pneumoniae challenge, and thbs1(-/-) neutrophils showed enhanced intracellular microbial killing that was abrogated with recombinant TSP-1 administration or WT serum. Thbs1(-/-) neutrophils exhibited enhanced NE and CG enzymatic activity, and a peptide corresponding to amino-acid residues 793-801 within the type-III repeat domain of TSP-1 bridled neutrophil proteolytic function and microbial killing in vitro. Thus, TSP-1 restrains proteolytic action during neutrophilic inflammation elicited by K. pneumoniae, providing a mechanism that may regulate the microbial killing arsenal.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Olonisakin
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hulver
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sayeed
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Yu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Gregory
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Kochman
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Chen
authors.affiliation: 1] Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] The Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Mallampalli
authors.affiliation: Department of Cell Biology and Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: Department of Cell Biology and Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Shapiro
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ray
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ray
authors.affiliation: 1] Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D056649:Cathepsin G / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007710:Klebsiella Infections / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000276:immunology*; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D016897:Respiratory Burst / Q000235:genetics / Q000276:immunology; D057057:Serine Proteases / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D019700:Thrombospondin 1 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D057057:Serine Proteases; D056649:Cathepsin G; D019272:Leukocyte Elastase