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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4478-4486.
Prepublished online as a Blood First Edition Paper on February 1, 2007; DOI 10.1182/blood-2006-02-001719.
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PHAGOCYTES
Neutrophil elastase depends on serglycin proteoglycan for localization in granules
Carsten U. Niemann1,
Magnus Åbrink2,
Gunnar Pejler2,
Rikke L. Fischer3,
Erik I. Christensen4,
Stefan D. Knight5, and
Niels Borregaard1
1 Rigshospitalet, Department of Hematology, Granulocyte Research Laboratory, University of Copenhagen, Denmark;
2 Swedish University of Agricultural Sciences, Department of Molecular Biosciences, Uppsala Biomedical Centre, Sweden;
3 National Center for Antimicrobials and Infectious Control, Statens Serum Institut, Copenhagen, Denmark;
4 Department of Cell Biology, Institute of Anatomy, University of Aarhus, Denmark;
5 Swedish University of Agricultural Sciences, Department of Molecular Biology, Uppsala Biomedical Centre, Sweden
Granule proteins play a major role in bacterial killing by neutrophils. Serglycin proteoglycan, the major intracellular proteoglycan of hematopoietic cells, has been proposed to play a role in sorting and packing of granule proteins. We examined the content of major neutrophil granule proteins in serglycin knockout mice and found neutrophil elastase absent from mature neutrophils as shown by activity assay, Western blotting, and immunocytochemistry, whereas neutrophil elastase mRNA was present. The localization of other neutrophil granule proteins did not differ between wild-type and serglycin knockout mice. Differential counts and neutrophil ultrastructure were unaffected by the lack of serglycin, indicating that defective localization of neutrophil elastase does not induce neutropenia itself, albeit mutations in the neutrophil elastase gene can cause severe congenital neutropenia or cyclic neutropenia. The virulence of intraperitoneally injected Gram-negative bacteria (Klebsiella pneumoniae) was increased in serglycin knockout mice compared with wild-type mice, as previously reported for neutrophil elastase knockout mice. Thus, serglycin proteoglycan has an important role in localizing neutrophil elastase in azurophil granules of neutrophils, while localization of other granule proteins must be mediated by other mechanisms.

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