The circadian clock gene BMAL1 modulates autoimmunity features in lupus

作者：Shuichiro Nakabo, Donavon Sandoval-Heglund, Norio Hanata, Stephen R. Brooks, Victoria Hoffmann, Mingzeng Zhang, William G Ambler, Zerai Manna, Elaine Poncio, Sarfaraz Hasni, Shamima Islam, Stefania Dell’Orso, Mariana J. Kaplan · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1465185 · 被引用次数：8 · 研究领域：Circadian rhythm and melatonin、Digestive system and related health、Spaceflight effects on biology

Objectives An important pathogenic role for neutrophils in systemic lupus erythematosus (SLE) has been proposed. Neutrophils that lack brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 ( Bmal1 ), one of the clock genes, are defective in aging and proinflammatory responses. We assessed the role of Bmal1 in clinical and immunologic manifestations of murine lupus and in human SLE neutrophils. Methods Myeloid-conditional Bmal1 knockout mice ( Bmal1 Mye−/− ) and wild type (WT) were treated with epicutaneous TLR7/8 agonist (imiquimod; IMQ) for 6 weeks to induce a lupus phenotype. Upon euthanasia, immune responses, autoantibodies and renal manifestations were evaluated. NET formation and gene expression of bone marrow (BM)-derived murine neutrophils were evaluated. BMAL1 expression was quantified in SLE neutrophils and compared with clinical disease. Results IMQ-treated Bmal1 Mye−/− and WT displayed comparable systemic inflammation. While renal function did not differ, serum anti-dsDNA levels and renal immune complex deposition were significantly increased in Bmal1 Mye−/− . While no differences were observed in NET formation, expression levels of April in BM neutrophils were significantly higher in Bmal1 Mye−/− . Bulk RNA-sequence data showed that BM neutrophils in IMQ-treated Bmal1 Mye−/− were relatively immature when compared with IMQ-treated WT. BM showed an enhanced April protein expression in Bmal1 Mye−/− mice. BMAL1 levels in human SLE peripheral blood neu...