Mice with a DC-specific deletion of the transcriptional repressor B lymphocyte–induced maturation protein-1 (Blimp1) exhibit a lupus-like phenotype, secondary to enhanced DC production of IL-6. Here we explored further phenotypic changes in Blimp1-deficient DCs, the molecular mechanism underlying these changes, and their relevance to human disease. Blimp1-deficient DCs exhibited elevated expression of MHC II, and exposure to TLR agonists increased secretion of proinflammatory cytokines. This phenotype reflects enhanced expression of the microRNA let-7c, which is regulated by BLIMP1. Let-7c reciprocally inhibited Blimp1 and also blocked LPS-induced suppressor of cytokine signaling-1 (SOCS1) expression, contributing to the proinflammatory phenotype of Blimp1-deficient DCs. DCs from Blimp1 SLE-risk allele carriers exhibited analogous phenotypic changes, including decreased BLIMP1 expression, increased let-7c expression, and increased expression of proinflammatory cytokines. These results suggest that let-7c regulates DC phenotype and confirm the importance of BLIMP1 in maintaining tolerogenic DCs in both mice and humans.
(A) Lentivirus carrying either control miRNA or let-7c miRNA was transduced into BM-DCs prepared from control mice. GFP+-transduced DCs were sorted, and the level of let-7c was measured by qPCR. (B) miRNA-transduced BM-DCs were cultured with or without LPS (1 μg/ml) overnight. Supernatants were harvested and IL-6 was measured by ELISA. (C) Level of SOCS1 was measured by qPCR from control miRNA or let-7c miRNA–transduced BM-DCs. Relative expression was calculated compared with β2m. Open bar represents control miRNA, and gray bar represents let-7c–transduced BM-DCs. Values are expressed as mean ± SEM, n = 4 per group.