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

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, A. Mócsai, Martin Herrmann, Georg Schett, Rikard Holmdahl, Markus H. Hoffmann

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
JournalJCI insight
Volume2
Issue number10
DOIs
Publication statusPublished - May 18 2017

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Neutrophils
Systemic Lupus Erythematosus
Autoantibodies
Alkanes
Extracellular Traps
Peritoneum
Glomerulonephritis
Intraperitoneal Injections
Autoimmunity
Cell Death
pristane
arginine deiminase
Therapeutics

Keywords

  • Autoimmunity
  • Inflammation

Cite this

Kienhöfer, D., Hahn, J., Stoof, J., Csepregi, J. Z., Reinwald, C., Urbonaviciute, V., ... 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

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. / Kienhöfer, Deborah; Hahn, Jonas; Stoof, Julia; Csepregi, Janka Zsófia; Reinwald, Christiane; Urbonaviciute, Vilma; Johnsson, Caroline; Maueröder, Christian; Podolska, Malgorzata J.; Biermann, Mona H.; Leppkes, Moritz; Harrer, Thomas; Hultqvist, Malin; Olofsson, Peter; Munoz, Luis E.; Mócsai, A.; Herrmann, Martin; Schett, Georg; Holmdahl, Rikard; Hoffmann, Markus H.

In: JCI insight, Vol. 2, No. 10, 18.05.2017.

Research output: Contribution to journalArticle

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, Mócsai, A, Herrmann, M, Schett, G, Holmdahl, R & Hoffmann, MH 2017, 'Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps', JCI insight, vol. 2, no. 10. https://doi.org/10.1172/jci.insight.92920
Kienhöfer, Deborah ; Hahn, Jonas ; Stoof, Julia ; Csepregi, Janka Zsófia ; Reinwald, Christiane ; Urbonaviciute, Vilma ; Johnsson, Caroline ; Maueröder, Christian ; Podolska, Malgorzata J. ; Biermann, Mona H. ; Leppkes, Moritz ; Harrer, Thomas ; Hultqvist, Malin ; Olofsson, Peter ; Munoz, Luis E. ; Mócsai, A. ; Herrmann, Martin ; Schett, Georg ; Holmdahl, Rikard ; Hoffmann, Markus H. / Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. In: JCI insight. 2017 ; Vol. 2, No. 10.
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AU - Urbonaviciute, Vilma

AU - Johnsson, Caroline

AU - Maueröder, Christian

AU - Podolska, Malgorzata J.

AU - Biermann, Mona H.

AU - Leppkes, Moritz

AU - Harrer, Thomas

AU - Hultqvist, Malin

AU - Olofsson, Peter

AU - Munoz, Luis E.

AU - Mócsai, A.

AU - Herrmann, Martin

AU - Schett, Georg

AU - Holmdahl, Rikard

AU - Hoffmann, Markus H.

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N2 - 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.

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