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Kienhöfer D, Hahn J, Stoof J, et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight. 2017;2(10)doi: 10.1172/jci.insight.92920.
Kienhöfer, D., Hahn, J., Stoof, J., Csepregi, J. Z., Reinwald, C., Urbonaviciute, V., Johnsson, C., Maueröder, C., Podolska, M. J., Biermann, M. H., Leppkes, M., Harrer, T., Hultqvist, M., Olofsson, P., Munoz, L. E., Mocsai, A., Herrmann, M., Schett, G., Holmdahl, R., & Hoffmann, M. H. (2017). Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI insight, 2(10), . https://doi.org/10.1172/jci.insight.92920
Kienhöfer, Deborah, et al. "Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps." JCI insight vol. 2,10 (2017). doi: https://doi.org/10.1172/jci.insight.92920
Kienhöfer D, Hahn J, Stoof J, Csepregi JZ, Reinwald C, Urbonaviciute V, Johnsson C, Maueröder C, Podolska MJ, Biermann MH, Leppkes M, Harrer T, Hultqvist M, Olofsson P, Munoz LE, Mocsai A, Herrmann M, Schett G, Holmdahl R, Hoffmann MH. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.92920. eCollection 2017 May 18. PMID: 28515366; PMCID: PMC5436535.
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JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.92920. eCollection 2017 May 18.

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

JCI insight

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

Affiliations

  1. Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany.
  2. Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 1 - Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, Erlangen, Germany.
  3. Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  4. Redoxis AB, Medicon Village Lund, Sweden.
  5. Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.
  6. ProNoxis AB, Medicon Village Lund, Sweden.

PMID: 28515366 PMCID: PMC5436535 DOI: 10.1172/jci.insight.92920

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.

Keywords: Autoimmunity; Inflammation

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