title: IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis.
abstract: Premature atherosclerosis is a severe complication of lupus and other systemic autoimmune disorders. Gain-of-function polymorphisms in IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing lupus, and IRF5 deficiency in lupus mouse models ameliorates disease. However, whether IRF5 deficiency also protects against atherosclerosis development in lupus is not known. In this study, we addressed this question using the gld.apoE(-/-) mouse model. IRF5 deficiency markedly reduced lupus disease severity. Unexpectedly, despite the reduction in systemic immune activation, IRF5-deficient mice developed increased atherosclerosis and also exhibited metabolic dysregulation characterized by hyperlipidemia, increased adiposity, and insulin resistance. Levels of the atheroprotective cytokine IL-10 were reduced in aortae of IRF5-deficient mice, and in vitro studies demonstrated that IRF5 is required for IL-10 production downstream of TLR7 and TLR9 signaling in multiple immune cell types. Chimera studies showed that IRF5 deficiency in bone marrow-derived cells prevents lupus development and contributes in part to the increased atherosclerosis. Notably, IRF5 deficiency in non-bone marrow-derived cells also contributes to the increased atherosclerosis through the generation of hyperlipidemia and increased adiposity. Together, our results reveal a protective role for IRF5 in lupus-associated atherosclerosis that is mediated through the effects of IRF5 in both immune and nonimmune cells. These findings have implications for the proposed targeting of IRF5 in the treatment of autoimmune disease as global IRF5 inhibition may exacerbate cardiovascular disease in these patients.
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Watkins
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Kei
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Gabriella E
authors.initials: GE
authors.lastname: Wilson
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Tamar
authors.initials: T
authors.lastname: Aprahamian
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Yao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Maganto-Garcia
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Prachi
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Lillian
authors.initials: L
authors.lastname: Oberlander
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Bari
authors.initials: B
authors.lastname: Laskow
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Hanni
authors.initials: H
authors.lastname: Menn-Josephy
authors.affiliation: Endocrinology Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Pierre
authors.initials: P
authors.lastname: Duffau
authors.affiliation: Endocrinology Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
authors.affiliation: Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Ramon G
authors.initials: RG
authors.lastname: Bonegio
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; irifkin@bu.edu.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse