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 negative feedback loop between Blimp1 and let-7c regulates levels of SOCS1 and IL-6, and may explain the function of Blimp1 risk alleles. The effects of Blimp1 KO and/or siRNA knockdown (see experiments in Figure 1) remove inhibition of let-7c, thus leading to reduced SOCS1 expression (see experiments in Figure 3). Conversely, overexpression of Blimp1 leads to reduced let-7c expression and reduced IL-6 expression, either through enhanced SOCS1 expression or through direct effects of Blimp1 on IL-6 (data in Figure 4). Finally, transfection of let-7c reduces SOCS1 expression, and leads to increased expression of IL-6 (see data in Figure 5). These relationships are consistent with data from human cells (see Figure 6), which also relate lower Blimp1 levels to increased HLA-DR expression, possibly through release of inhibition of the CIITA transcription factor.