Lupus and proliferative nephritis are PAD4 independent in murine models
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
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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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 6

Cl-Amidine does not ameliorate kidney damage in the SLE serum–transfer model.

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Cl-Amidine does not ameliorate kidney damage in the SLE serum–transfer m...
Nephritis was induced by the intravenous injection of systemic lupus erythematosus (SLE) serum into FcγRIIAγ–/–Mac-1–/– mice. (A) Albuminuria at the indicated days after SLE sera injection in mice treated daily with either vehicle (PBS) or Cl-Amidine. Urine albumin was normalized to urine creatinine (day 0 vehicle n = 9, Cl-Amidine n = 10; day 7 vehicle n = 7, Cl-Amidine n = 9; day 10 vehicle n = 10, Cl-Amidine n = 10; day 14 vehicle n = 5, Cl-Amidine n = 6 mice per group). (B) Kidney pathology of mice in (A) at 14 days after serum transfer. (C) Quantification of renal macrophages (CD45+CD11b+F4/80+) and neutrophils (CD45+Gr1hiLy6B.2+) in kidneys at day 10 (n = 4 mice per group) and 14 (vehicle n = 5; Cl-Amidine n = 6 mice per group) of mice in A. Bars represent the median ± interquartile range (A and B). A Mann-Whitney U test was performed to determine statistical significance. In panel C, bars graphs denote the mean ± SEM and a Welch’s t test was performed to determine statistical significance. NS, not significant.