The circadian clock gene BMAL1 modulates autoimmunity features in lupus

Area of Science:

• Immunology
• Chronobiology
• Rheumatology

Background:

• Neutrophils play a key role in systemic lupus erythematosus (SLE) pathogenesis.
• Clock genes, such as brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1), regulate neutrophil function.
• Defects in Bmal1 impact aging and inflammatory responses.

Purpose of the Study:

• To investigate the role of Bmal1 in neutrophils in the context of murine lupus.
• To examine the clinical and immunological manifestations of lupus in mice lacking Bmal1 in myeloid cells.
• To analyze Bmal1 expression in human SLE neutrophils and its correlation with disease activity.

Main Methods:

• Myeloid-conditional Bmal1 knockout mice (Bmal1Mye-/-) and wild-type (WT) littermates were treated with imiquimod (IMQ) to induce lupus.
• Immune responses, autoantibodies, renal manifestations, neutrophil extracellular trap (NET) formation, and gene expression were evaluated.
• BMAL1 expression in human SLE neutrophils was quantified and compared with clinical data.

Main Results:

• While systemic inflammation was comparable, Bmal1Mye-/- mice showed increased anti-dsDNA antibodies and renal immune complex deposition.
• Neutrophils from Bmal1Mye-/- mice exhibited higher expression of April and immaturity.
• Human SLE neutrophils with lower BMAL1 levels correlated with higher C3 and lower anti-dsDNA levels.

Conclusions:

• Bmal1 deficiency in neutrophils is associated with increased lupus nephritis severity.
• Perturbations in neutrophil circadian rhythm, specifically Bmal1, can contribute to SLE pathogenesis.
• Bmal1 expression in neutrophils may serve as a biomarker for SLE disease activity.