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 9

IsoLG scavenging reduces blood pressure and systemic autoimmunity in the NZBWF1 mouse model of SLE.

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IsoLG scavenging reduces blood pressure and systemic autoimmunity in the...
Animals were sacrificed at 32 weeks, and single-cell suspensions were prepared from the spleen, kidney, and bone marrow and analyzed by flow cytometry. (A) Representative histogram displaying the distribution of IsoLG adduct–containing splenic DCs. (B) Quantitation of IsoLG adduct–containing splenic DCs. (C) Representative histogram displaying the distribution of IsoLG adduct–containing bone marrow plasma cells. (D) Quantitation of IsoLG adduct–containing bone marrow plasma cells. Radiotelemeters were implanted in 30-week-old mice. Blood pressure was measured over a 3-day period prior to sacrifice at 32 weeks old. Day and night cycles are represented for (E) systolic, (F) diastolic, and (G) mean arterial pressures. Flow cytometry was performed for quantitation of (H) kidney CD45+ and (I) kidney CD3+ T cells, (J) splenic CD3+ T cells, (K) splenic DCs, and (L) bone marrow plasma cells. (M) Urinary NGAL and (N) BUN were quantitated by ELISA. Data from B, D, and H–M were analyzed by 1-way ANOVA or Brown-Forsythe and Welch ANOVA (n = 7–12, *P < 0.05, **P < 0.01, ****P < 0.0001). Blood pressure was analyzed using 2-way ANOVA (n = 5–9, #P < 0.001 NZBWF1 vs. NZBWF1 + 2-HOBA).