Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 98, Issue 1, Pages 99-106Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.4AB1114-543R
Keywords
serine; inflammation; autoimmune disease; skin; psoriasis
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Funding
- Polish National Science Center [2011/02/A/NZ5/00337]
- Foundation for Polish Science Grant [TEAM/2010-5]
- European Union within a European Regional Development Fund Award
- European Union [POIG.02.01.00-12-064/08]
- Polish Ministry of Science and Higher Education
- Intramural Research Program of the U.S. National Institutes of Health National Institute of Dental and Craniofacial Research
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Neutrophil extracellular traps (NETs), web-like DNA structures, provide efficient means of eliminating invading microorganisms but can also present a potential threat to its host because it is a likely source of autoantigens or by promoting bystander tissue damage. Therefore, it is important to identify mechanisms that inhibit NET formation. Neutrophil elastase (NE)dependent chromatin decondensation is a key event in the release of NETs release. We hypothesized that inhibitors of NE, secretory leukocyte protease inhibitor (SLPI) and alpha(1)-proteinase inhibitor (alpha(1)-PI), has a role in restricting NET generation. Here, we demonstrate that exogenous human SLPI, but not alpha(1)-PI markedly inhibited NET formation in human neutrophils. The ability of exogenous SLPI to attenuate NET formation correlated with an inhibition of a core histone, histone 4 (H4), cleavage, and partial dependence on SLPI-inhibitory activity against NE. Moreover, neutrophils from SLPI (/) mice were more efficient at generating NETs than were neutrophils from wild-type mice in vitro, and in experimental psoriasis in vivo. Finally, endogenous SLPI colocalized with NE in the nucleus of human neutrophils in vitro, as well as in vivo in inflamed skin of patients with psoriasis. Together, these findings support a controlling role for SLPI in NET generation, which is of potential relevance to infectious and autoinflammatory diseases.
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