JCI Insight (Jul 2022)

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

Journal volume & issue
Vol. 7, no. 13

Abstract

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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.

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