The circadian clock gene BMAL1 modulates autoimmunity features in lupus.

Abstract

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 (), one of the clock genes, are defective in aging and proinflammatory responses. We assessed the role ofin clinical and immunologic manifestations of murine lupus and in human SLE neutrophils. METHODS: Myeloid-conditionalknockout mice () 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.expression was quantified in SLE neutrophils and compared with clinical disease. RESULTS: IMQ-treatedand WT displayed comparable systemic inflammation. While renal function did not differ, serum anti-dsDNA levels and renal immune complex deposition were significantly increased in. While no differences were observed in NET formation, expression levels ofin BM neutrophils were significantly higher in. Bulk RNA-sequence data showed that BM neutrophils in IMQ-treatedwere relatively immature when compared with IMQ-treated WT. BM showed an enhanced April protein expression inmice.levels in human SLE peripheral blood neutrophils correlated positively with serum C3 and negatively with serum anti-dsDNA levels. CONCLUSION: 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.