J Leukoc Biol. 2015 Jul;98(1):99-106.

The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps.

 

Zabieglo K1, Majewski P1, Majchrzak-Gorecka M1, Wlodarczyk A1, Grygier B1, Zegar A1, Kapinska-Mrowiecka M1, Naskalska A1, Pyrc K1, Dubin A1, Wahl SM1, Cichy J2.
  • 1Department 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.
  • 2Department 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.

 

Abstract

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. We hypothesized that inhibitor of NE, secretory leukocyte protease inhibitor (SLPI) and α1-Proteinase inhibitor (α1-PI), has a role in restricting NET generation. Here, we demonstrate that exogenous human SLPI, but not α1-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, 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.

KEYWORDS: autoimmune disease; inflammation; psoriasis; serine; skin

PMID: 25917460

 

Supplementary

Secretory Leukocyte Protease Inhibitor (SLPI) is a cysteine-rich, small cationic protein, best well-known for its anti-protease function. Although originally identified as a potent inhibitor of neutrophil elastase (NE) in epithelial secretion, it has become clear that the biological role of SLPI is much broader. We now understand that SLPI also possesses anti-microbial, anti-inflammatory and wound-healing activities. Despite its potential to limit excessive inflammation, not much is known about the role of SLPI in autoinflammatory diseases, such as psoriasis. Our work revealed that SLPI might have a previously unrecognized capacity to shape excessive inflammatory responses through restricting generation of Neutrophil Extracellular Traps (NETs), (1). In addition, our previous studies showed that SLPI might be a component of NETs in psoriatic skin and stimulate production of interferon type I (IFNI) from the adjacent plasmacytoid dendritic cells (PDCs), (2, 3). Although uncontrolled production of IFNI is associated with pathogenicity of autoimmune diseases, IFNI exerts multiply beneficial effects during inflammation, for example by supporting wound healing responses in the damaged tissues (4). Thus, SLPI appears to protect the host from autoinflammatory responses by restraining deposition of potentially harmful NETs in the inflamed tissues and fine-tuning IFNI levels (Fig, 1).

 

JC FIG1

Fig. 1. A model for SLPI regulation of NET formation and IFNI production in psoriatic skin. In activated neutrophils that infiltrate psoriatic skin, NE translocates to the nucleus where it contributes to chromatin decondensation. SLPI regulates NET formation at the level of chromatin decondensation by restricting NE-mediated cleavage of histones, but also through other yet to be identified mechanisms (1). In the absence, or low levels of SLPI, NETs deposited in sites of inflammation can inflict significant damage to skin, potentially providing and/or generating autoantigens and exacerbating inflammation (2). SLPI produced by cells in lesional psoriatic skin, for example kerationoctes, is sequestered on NETs (3). SLPI‑competent NETs support wound healing in the damaged skin in a manner dependent on production of IFNI by pDCs (4).

 

References:

  1. Zabieglo K., Majewski P., Majchrzak-Gorecka M. et al., The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps. J Leukoc Biol 2015, 98, 99-106.
  2. Skrzeczynska-Moncznik J., Wlodarczyk A., Banas M. et al., DNA structures decorated with cathepsin G/secretory leukocyte proteinase inhibitor stimulate IFNI production by plasmacytoid dendritic cells Am J Clin Exp Immunol Cell Biol 2013, 2, 186-194.
  3. Skrzeczynska-Moncznik J., Wlodarczyk A., Zabieglo K. et al., Secretory leukocyte proteinase inhibitor-competent DNA deposits are potent stimulators of plasmacytoid dendritic cells: implication for psoriasis. J Immunol 2012, 189, 1611-1617.
  4. Gregorio J., Meller S., Conrad C. et al., Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med 2010, 207, 2921-2930.

 

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