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) Blimp1-deficient BM-DCs were infected with Blimp1 or control gene-expressing lentivirus as described in Methods. The GFP+ or GFP– CD11c+ population (representative flow image is in the upper left panel) was sorted, and expression of Blimp1, let-7c, and IL-6 was measured by qPCR. Data represent the mean ± SEM of 3 independent experiments, with a total of 6 per group. (B and C) LPS-mediated SOCS1 induction was measured from control DCs, Blimp1-deficient DCs, Blimp1 or control gene–transduced Blimp1-deficient DCs by flow cytometry (B) and immunofluorescence (IF) (C). Bar graph represents the mean ± SEM of 3 independent experiments. For IF, BM-DCs were cultured in a chamber slide. IF images were taken using a Zeiss microscope at original magnification, ×100 (scale bar: 15 μm). (Single color images were presented in Supplemental Figure 5.)