The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps.
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 α(1)-proteinase inhibitor (α(1)-PI), has a role in restricting NET generation. Here, we demonstrate that exogenous human SLPI, but not α(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.
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Katarzyna
K
Zabieglo
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Pawel
P
Majewski
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Monika
M
Majchrzak-Gorecka
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Agnieszka
A
Wlodarczyk
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Beata
B
Grygier
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Aneta
A
Zegar
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Monika
M
Kapinska-Mrowiecka
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Antonina
A
Naskalska
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Krzysztof
K
Pyrc
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Adam
A
Dubin
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Sharon M
SM
Wahl
*Department of Immunology, Department of Microbiology, and Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Department of Dermatology, Zeromski Hospital, Kraków, Poland; and Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA joanna.cichy@uj.edu.pl.
Joanna
J
Cichy
D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D011565:Psoriasis / Q000276:immunology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000502:physiology*
C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor
autoimmune disease; inflammation; psoriasis; serine; skin