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Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection. Mucosal Immunol 2015 Jul;8(4):896-905

Date

12/11/2014

Pubmed ID

25492474

Pubmed Central ID

PMC4465063

DOI

10.1038/mi.2014.120

Scopus ID

2-s2.0-84932618977 (requires institutional sign-in at Scopus site)   43 Citations

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.

Author List

Zhao Y, Olonisakin TF, Xiong Z, Hulver M, Sayeed S, Yu MT, Gregory AD, Kochman EJ, Chen BB, Mallampalli RK, Sun M, Silverstein RL, Stolz DB, Shapiro SD, Ray A, Ray P, Lee JS

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cathepsin G
Cytotoxicity, Immunologic
Disease Models, Animal
Immunity, Innate
Klebsiella Infections
Klebsiella pneumoniae
Leukocyte Elastase
Lung
Mice
Mice, Knockout
Neutrophils
Peptides
Recombinant Proteins
Respiratory Burst
Serine Proteases
Spleen
Thrombospondin 1