Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus
David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison
David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison
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Research Article Inflammation

Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus

Abstract

We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.

Authors

David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison

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Figure 1

IsoLG adducts are enriched in monocytes of patients with SLE.

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IsoLG adducts are enriched in monocytes of patients with SLE. (A) Repres...
(A) Representative FACS plots displaying isoLG adduct containing CD11c+ PBMCs from a representative control and patient with SLE. Representative histograms displaying the distribution of isoLG adducts in (B) CD11c+ and (C) CD11c+CD86+ cells. Quantitation of IsoLG adduct–containing cells as a percentage of (D) CD11c+, (E) CD11c+CD86+, and (F) CD14+ cells. For B–F data were analyzed using 1-tailed Student’s t test or Mann-Whitney U test (n = 10–11, *P < 0.05). (G) Stable isotope dilution multiple reaction monitoring for mass spectrometry analysis of isoLG-lysine-lactam adduct in DCs. Representative liquid chromatography/mass spectrometry chromatographs from a representative patient. The top row shows multiple reaction monitoring chromatographs for isoLG lysine lactam in samples, while the bottom row shows multiple reaction monitoring chromatograph for [13C615N2] internal standard for the same samples. cps, counts per second; Rt, retention time. (H) Quantitation of isoLG-lysine in monocytes from a subset of SLE patients and controls. (I) Monocytes from SLE patients and controls were sorted. Superoxide was detected using HPLC to monitor conversion of dihydroethidium to the superoxide oxidation adduct 2-hydroxyethidium (2-HO-ET) and ethidium. (J) Quantitation of 2-HO-ET from SLE patients and controls. For H and J, comparisons were made with a 1-tailed Student’s t test (n = 4–6, *P < 0.05, **P < 0.01).