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

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.

Altered platelet proteome in lupus anticoagulant (LA)-positive patients—protein disulfide isomerase and NETosis as new players in LA-related thrombosis

“…All proteoforms are listed in Supplementary Table 1 and 3a-c). These proteins were selected because they were only altered in LA+ TE+ patients and have already been described to play a role in thrombus development from two completely different mechanistic perspectives [30][31][32] .…”

Neutrophil‐mediated vascular barrier injury: Role of neutrophil extracellular traps

“…121,122 These effects have moved researchers to target the proteolytic activity of NETs; the best characterized serine protease inhibitors, SerpinB1 and secretory leukocyte protease inhibitor, were recently reviewed in the context of NETs. 123 In contrast, in some conditions such as gout, proteases in NETs may limit inflammation by degrading cytokines and chemokines and restricting further PMN recruitment. 124 Given this, more studies are needed to fully elucidate the NET-specific effects of proteases on endothelial mechanisms.…”

“…Matrix metalloproteinases have also been identified to play a role in NET-mediated pathologies by degrading extracellular matrices and activating endothelial cells 123,124 . These effects have moved researchers to target the proteolytic activity of NETs; the best characterized serine protease inhibitors, SerpinB1 and secretory leukocyte protease inhibitor, were recently reviewed in the context of NETs 125 . In contrast, in some conditions such as gout, proteases in NETs may limit inflammation by degrading cytokines and chemokines and restricting further PMN recruitment 126 .…”

Antimicrobial and Attractant Roles for Chemerin in the Oral Cavity during Inflammatory Gum Disease

“…These include cathelicidins (LL37), α-defensins, β-defensins, histatins, and secretory leukocyte protease inhibitor (SLPI) (23–26). Because AMPs utilize different strategies to restrict microbial growth (24, 27), their diversity may be important for independently controlling the load, composition, and location of microbial communities in the oral cavity and for maintaining oral homeostasis.…”