Extracellular heme:DNA complexes promote oxidative stress and inflammation during lupus-associated hemolysis
Abstract
Hemolysis is associated with the release of damage-associated molecular patterns, including free heme and extracellular DNA (ecDNA). Using several mouse models of bleeding anemia and hemolysis, we demonstrate a significant increase in plasma ecDNA, independent of neutrophil extracellular trap formation. This ecDNA forms G-quadruplex (G4) structures, which we detected in both mice and patients with systemic lupus erythematosus. Catalytic complexes (DNAzymes) formed by G4 ecDNA and heme drive oxidative stress, tissue injury, and inflammation. In anemic mice lacking deoxyribonuclease 1L3 ( DNase1l3 −/− ), we found elevated polynucleosomal ecDNA in the plasma, reduced expression of the heme-degrading enzyme heme oxygenase-1 in macrophages, but also increased plasma creatinine, renal iron accumulation, and complement C3 deposition along elevated apoptosis and DNA damage. ecDNA isolated from these mice also triggered toll-like receptor 9-dependent inflammatory responses in vitro and in vivo. In summary, these findings suggest that concurrent release of heme and ecDNA during hemolysis promotes inflammation and tissue damage, contributing to lupus pathogenesis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Lubica Janovicova
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Monika Janikova
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Michal Pastorek
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Eva Csizmadia
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Cherith Yoder
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Alexandra Lesayova
Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University
Liam Geyer
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Vasileios C. Kyttaris
George C. Tsokos
Peter Celec
Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University
Barbara Wegiel
Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School