Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps
Deborah Kienhöfer, … , Rikard Holmdahl, Markus H. Hoffmann
Deborah Kienhöfer, … , Rikard Holmdahl, Markus H. Hoffmann
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e92920. https://doi.org/10.1172/jci.insight.92920.
View: Text | PDF
Research Article Inflammation

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

  • Text
  • PDF
Abstract

Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death–inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4–deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.

Authors

Deborah Kienhöfer, Jonas Hahn, Julia Stoof, Janka Zsófia Csepregi, Christiane Reinwald, Vilma Urbonaviciute, Caroline Johnsson, Christian Maueröder, Malgorzata J. Podolska, Mona H. Biermann, Moritz Leppkes, Thomas Harrer, Malin Hultqvist, Peter Olofsson, Luis E. Munoz, Attila Mocsai, Martin Herrmann, Georg Schett, Rikard Holmdahl, Markus H. Hoffmann

×

Figure 3

Impaired pristane-induced but enhanced spontaneous neutrophil extracellular trap (NET) formation in Ncf1** mice.

Options: View larger image (or click on image) Download as PowerPoint
Impaired pristane-induced but enhanced spontaneous neutrophil extracellu...
(A) Percentages of CD11b+Ly6ChiCCR2+ monocytes, CD11b+Ly6CintLy6G+ neutrophils, and CD11b+Ly6C– cells in the peritonea of BALB/c.Ncf1** and WT mice before and 14 days after injection of pristane. Scatter plots show individual values, means, and SEM (n = 5–8). ***P < 0.001 as determined by ANOVA with Bonferroni post-hoc test. (B) Representative fluorescence microscopy images and (C) quantification of peritoneal cells isolated 1 day after injection of pristane and stained for DNA with propidium iodide (PI, red) and for citrullinated histone H3 (citH3, green). Scale bars: 100 μm. Scatter plot shows individual values, means, and SEM (n = 4–8). PI+citH3+ events represent cells having undergone NETosis. ***P < 0.001 as determined by ANOVA with Bonferroni post-hoc test. (D) Concentrations of selected cytokines and chemokines in peritoneal lavages of BALB/c.Ncf1** and WT mice 0 and 14 days after injection of pristane. Scatter plot shows individual values, means, and SEM (n = 10). **P < 0.01, ***P < 0.001 as determined by ANOVA with Bonferroni post-hoc test. (E) Quantitative analysis of NETing cells in blood drawn from untreated BALB/c WT and Ncf1** mice. Scatter plot shows individual values, mean, and SEM of percentages of cells having undergone NET formation (PI+citH3+ events) in 7 to 8 mice. *P < 0.05 as determined by 2-tailed Student’s t test. (F) Percentage of CD11b+Ly6Cint Ly6G+ cells in the peripheral blood mononuclear cell fraction after density gradient centrifugation performed on blood of BALB/c WT and Ncf1** mice. Scatter plot shows individual values, mean, and SEM, n = 9. *P < 0.05 as determined by 2-tailed Student’s t test using Welch’s correction for unequal variances. LDG, low-density granulocyte. (G) Spontaneous and antimycin A–induced (AMA-induced) mitochondrial ROS production (MitoSOX mean fluorescence intensity [MFI]) in BALB/c WT and Ncf1** mice. Scatter plots show individual values, means, and SEM of 4 to 5 animals. n.s., not significant.

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts