Regulation and Mechanism of Deleted in Breast Cancer‐1 on Dendritic Cell Function in Systemic Lupus Erythematosus

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs and involving both innate and adaptive immunity. Dendritic cells (DCs) play a crucial role in linking innate and adaptive immune responses, and therefore they deeply participate in the initiation and development of SLE. Deleted in breast cancer‐1 (DBC1) is a negative regulator of deacetylase SIRT1 (the mammalian homolog of silent information regulator 1) and involves in tissue inflammation. Roles of DBC1 in immune cells remain largely unknown, especially in DCs. We here identified that DBC1 is upregulated in activated DCs, and DBC1 deficiency weakened DC maturation while promoting B7‐H1 expression. DC conditional knockout of DBC1 ameliorated murine lupus pathology by decreasing autoantibodies, complement C3, plasma cells, and follicular T helper (Tfh) cells, whereas promoting regulatory T‐cell development. We further demonstrated that Dbc1 −/− DC lowered proinflammatory cytokine secretion such as IL‐4, IL‐6, and IL‐12, and reduced signal transducer and activator of transcription 5 (STAT5) signal. With STAT5 overexpression, the protective effect by Dbc1 −/− DC was abolished in the lupus model. Therefore, targeting the DBC1‐STAT5 axis in DCs diversifies the therapeutic strategies for SLE.