Lupus and proliferative nephritis are PAD4 independent in murine models
Rachael A. Gordon, … , Tanya N. Mayadas, Mark J. Shlomchik
Rachael A. Gordon, … , Tanya N. Mayadas, Mark J. Shlomchik
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e92926. https://doi.org/10.1172/jci.insight.92926.
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Research Article Immunology

Lupus and proliferative nephritis are PAD4 independent in murine models

Abstract

Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed that inhibition of NETs by targeting the NADPH oxidase complex via cytochrome b-245, β polypeptide (cybb) deletion exacerbated disease in the MRL.Faslpr lupus mouse model. While these data challenge the paradigm that NETs promote lupus, it is conceivable that global regulatory properties of cybb and cybb-independent NETs confound these findings. Furthermore, recent reports indicate that inhibitors of peptidyl arginine deiminase, type IV (Padi4), a distal mediator of NET formation, improve lupus in murine models. Here, to clarify the contribution of NETs to SLE, we employed a genetic approach to delete Padi4 in the MRL.Faslpr model and used a pharmacological approach to inhibit PADs in both the anti–glomerular basement membrane model of proliferative nephritis and a human-serum-transfer model of SLE. In contrast to prior inhibitor studies, we found that deletion of Padi4 did not ameliorate any aspect of nephritis, loss of tolerance, or immune activation. Pharmacological inhibition of PAD activity had no effect on end-organ damage in inducible models of glomerulonephritis. These data provide a direct challenge to the concept that NETs promote autoimmunity and target organ injury in SLE.

Authors

Rachael A. Gordon, Jan M. Herter, Florencia Rosetti, Allison M. Campbell, Hiroshi Nishi, Michael Kashgarian, Sheldon I. Bastacky, Anthony Marinov, Kevin M. Nickerson, Tanya N. Mayadas, Mark J. Shlomchik

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Figure 4

Cl-Amidine effectively reduces NET formation in the cremaster muscle following the reverse passive Arthus (RPA) reaction.

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Cl-Amidine effectively reduces NET formation in the cremaster muscle fol...
The RPA reaction was induced in the cremaster muscle. Leukocyte recruitment and neutrophil extracellular trap (NET) formation was evaluated 3 hours later. Data are represented as a function of Padi4 genotype or Cl-Amidine administration. (A) NET-like structures were visualized with Sytox green using intravital microscopy. Representative micrographs are shown. Scale bar: 100 μm. (B and C) Number of leukocytes adherent to the vessel wall of animals in A. Number of transmigrated leukocytes within 75 μm of each side of the vessel over 100 μm. Bars graphs denote the mean ± SEM and a Welch’s t test was performed to determine statistical significance (A [left] and B vehicle and Cl-Amidine treated n = 5 mice per group, A [right] and C vehicle n = 3 mice per group; Cl-Amidine n = 4 mice per group [right panel of C]). *P < 0.05. NS, not significant.