Skip to main content

ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1465185

The circadian clock gene BMAL1 modulates autoimmunity features in lupus

Provisionally accepted
Shuichiro Nakabo Shuichiro Nakabo 1Donavon Sandoval-Heglund Donavon Sandoval-Heglund 1Norio Hanata Norio Hanata 1Stephen R Brooks Stephen R Brooks 1VIctoria Hoffman VIctoria Hoffman 2Mingzeng Zhang Mingzeng Zhang 1William Ambler William Ambler 1Zerai Manna Zerai Manna 1Elaine POncio Elaine POncio 1Sarfaraz Hasni Sarfaraz Hasni 1Shamima Islam Shamima Islam 1Stefania Dell'Orso Stefania Dell'Orso 1Mariana Julieta Kaplan Mariana Julieta Kaplan 1*
  • 1 Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH), Bethesda, MI, United States
  • 2 Office of the Director (NIH), Bethesda, Maryland, United States

The final, formatted version of the article will be published soon.

    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.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.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 RNAsequence data showed that BM neutrophils in IMQ-treated Bmal1 Mye-/-were relatively immature when compared to IMQ-treated WT. BM showed enhanced April protein expression in Bmal1 Mye-/- mice. BMAL1 levels in human SLE peripheral blood neutrophils correlated positively with serum C3 and negatively with serum anti-dsDNA levels.Bmal1 is associated with lower disease activity in SLE. These results indicate that perturbation in the circadian rhythm of neutrophils can have pathogenic consequences in SLE.

    Keywords: systemic lupus erythematosus, Neutrophils, Autoantibody, clock gene, bmal1, April

    Received: 15 Jul 2024; Accepted: 28 Oct 2024.

    Copyright: © 2024 Nakabo, Sandoval-Heglund, Hanata, Brooks, Hoffman, Zhang, Ambler, Manna, POncio, Hasni, Islam, Dell'Orso and Kaplan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Mariana Julieta Kaplan, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH), Bethesda, 48109, MI, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.