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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

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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 1

Padi4 genotype does not impact lupus nephritis, dermatitis, or lymphadenopathy/splenomegaly.

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Padi4 genotype does not impact lupus nephritis, dermatitis, or lymphade...
(A) Proteinuria (left panel) and dermatitis (right panel) scores (Padi4–/– males n = 13; Padi4+/– males n = 18; Padi4+/+ males n = 18; Padi4–/– females n = 9; Padi4+/– females n = 22; Padi4+/+ females n = 16). (B) Glomerulonephritis (left panel) and interstitial nephritis (right panel) scores. (C) Spleen (upper panel) and axillary lymph node (lower panel) weights. Scores and weights are represented as a function of Padi4 genotype and gender at 17 weeks of age. Bars represent the median ± interquartile range. A Kruskal-Wallis test with post-hoc Dunn’s test was performed to determine statistical significance within each gender (Padi4–/– males n = 13; Padi4+/– males n = 19; Padi4+/+ males n = 18; Padi4–/– females n = 8; Padi4+/– females n = 22; Padi4+/+ females n = 16 unless otherwise indicated). NS, not significant.
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