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Review
. 2016 Jun 30:7:261.
doi: 10.3389/fimmu.2016.00261. eCollection 2016.

Inhibitors of Serine Proteases in Regulating the Production and Function of Neutrophil Extracellular Traps

Pawel Majewski  1 , Monika Majchrzak-Gorecka  1 , Beata Grygier  1 , Joanna Skrzeczynska-Moncznik  1 , Oktawia Osiecka  1 , Joanna Cichy  1
Affiliations
Review

Inhibitors of Serine Proteases in Regulating the Production and Function of Neutrophil Extracellular Traps

Pawel Majewski et al. Front Immunol. .

Abstract

Neutrophil extracellular traps (NETs), DNA webs released into the extracellular environment by activated neutrophils, are thought to play a key role in the entrapment and eradication of microbes. However, NETs are highly cytotoxic and a likely source of autoantigens, suggesting that NET release is tightly regulated. NET formation involves the activity of neutrophil elastase (NE), which cleaves histones, leading to chromatin decondensation. We and others have recently demonstrated that inhibitors of NE, such as secretory leukocyte protease inhibitor (SLPI) and SerpinB1, restrict NET production in vitro and in vivo. SLPI was also identified as a NET component in the lesional skin of patients suffering from the autoinflammatory skin disease psoriasis. SLPI-competent NET-like structures (a mixture of SLPI with neutrophil DNA and NE) stimulated the synthesis of interferon type I (IFNI) in plasmacytoid dendritic cells (pDCs) in vitro. pDCs uniquely respond to viral or microbial DNA/RNA but also to nucleic acids of "self" origin with the production of IFNI. Although IFNIs are critical in activating the antiviral/antimicrobial functions of many cells, IFNIs also play a role in inducing autoimmunity. Thus, NETs decorated by SLPI may regulate skin immunity through enhancing IFNI production in pDCs. Here, we review key aspects of how SLPI and SerpinB1 can control NET production and immunogenic function.

Keywords: SLPI; neutrophil elastase; neutrophil extracellular traps; plasmacytoid dendritic cells; psoriasis; serpin B1.

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Figures

Figure 1
Figure 1
Proposed involvement of SerpinB1 and SLPI in NET formation and immunogenic function. (1) In resting neutrophils, NE localizes to primary granules, whereas SerpinB1 and SLPI localize to the cytoplasm and/or secondary granules. (2) In activated neutrophils that infiltrate psoriatic skin, NE translocates to the nucleus, where it contributes to chromatin decondensation. SLPI and SerpinB1 translocate independently to the nucleus, where they regulate NET formation at the level of chromatin decondensation. Once in the nucleus, SLPI restricts the NE-mediated cleavage of histones, whereas SerpinB1 limits chromatin decondensation through other, yet-to-be-identified mechanisms. (3) The inhibition of NET formation is partial, and the decondensed chromatin containing NE, as well as SerpinB1 and SLPI, is deposited into the extracellular milieu. (4) SLPI produced by keratinocytes in lesional psoriatic skin is sequestered on NETs. (5) SLPI-competent NETs stimulate the pro-inflammatory and/or skin healing function that results from skin damage through the production of IFNI by pDCs.
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