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Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation
Christian C. Yost, … , Andrew S. Weyrich, Guy A. Zimmerman
Christian C. Yost, … , Andrew S. Weyrich, Guy A. Zimmerman
Published September 6, 2016
Citation Information: J Clin Invest. 2016;126(10):3783-3798. https://doi.org/10.1172/JCI83873.
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Research Article Inflammation Article has an altmetric score of 245

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

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Abstract

Neutrophil granulocytes, also called polymorphonuclear leukocytes (PMNs), extrude molecular lattices of decondensed chromatin studded with histones, granule enzymes, and antimicrobial peptides that are referred to as neutrophil extracellular traps (NETs). NETs capture and contain bacteria, viruses, and other pathogens. Nevertheless, experimental evidence indicates that NETs also cause inflammatory vascular and tissue damage, suggesting that identifying pathways that inhibit NET formation may have therapeutic implications. Here, we determined that neonatal NET-inhibitory factor (nNIF) is an inhibitor of NET formation in umbilical cord blood. In human neonatal and adult neutrophils, nNIF inhibits key terminal events in NET formation, including peptidyl arginine deiminase 4 (PAD4) activity, neutrophil nuclear histone citrullination, and nuclear decondensation. We also identified additional nNIF-related peptides (NRPs) that inhibit NET formation. nNIFs and NRPs blocked NET formation induced by pathogens, microbial toxins, and pharmacologic agonists in vitro and in mouse models of infection and systemic inflammation, and they improved mortality in murine models of systemic inflammation, which are associated with NET-induced collateral tissue injury. The identification of NRPs as neutrophil modulators that selectively interrupt NET generation at critical steps suggests their potential as therapeutic agents. Furthermore, our results indicate that nNIF may be an important regulator of NET formation in fetal and neonatal inflammation.

Authors

Christian C. Yost, Hansjörg Schwertz, Mark J. Cody, Jared A. Wallace, Robert A. Campbell, Adriana Vieira-de-Abreu, Claudia V. Araujo, Sebastian Schubert, Estelle S. Harris, Jesse W. Rowley, Matthew T. Rondina, James M. Fulcher, Curry L. Koening, Andrew S. Weyrich, Guy A. Zimmerman

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Figure 3

nNIF and the NRP CRISPP inhibit in vitro NET formation triggered by a spectrum of NET-inducing agonists.

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nNIF and the NRP CRISPP inhibit in vitro NET formation triggered by a sp...
Neutrophils from venous blood of healthy adults were preincubated in medium alone or with nNIF, CRISPP, or CRISPP-SCR (all 1 nM) for 1 hour, then activated with the indicated agonists (n ≥ 3 for each). NET formation (red fluorescence, yellow arrows) was assessed after 1 hour of incubation as in Figure 1A. All data are represented as ± SEM. In A, B, C, and E, control values arbitrarily set at 1 are indicated by dashed red lines. One-way ANOVA with Tukey’s post hoc testing was applied in A, B, C, and E. nNIF was not studied in C or D. (A) LPS, 100 ng/ml. **P < 0.05, LPS and CRISPP-SCR/LPS compared with control, †P < 0.05, CRISPP/LPS and nNIF/LPS compared with both LPS and CRISPP-SCR/LPS. (B) PMA (20 nM). *P < 0.05, both nNIF/PMA and CRISPP/PMA compared with PMA or CRISPP-SCR/PMA; **P < 0.01, CRISPP/PMA versus CRISPP-SCR/PMA. (C) S. aureus (SA; MOI 100:1). *P < 0.05, CRISPP/SA compared with SA or CRISPP-SCR/SA. (D) Dengue virus (MOI 0.05:1). Viral culture medium alone served as a “mock” control (left panels) for dengue virus. Following incubation, the PMNs were immediately fixed in the incubation medium (2% PFA) prior to imaging, and quantitation of histone H3 release was not possible. (E) Heme (1 μM). *P < 0.05, heme, LPS, and CRISPP-SCR/heme versus control; †P < 0.05, CRISPP/heme versus heme. Original magnification, ×20. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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