MicroRNA-mediated modulations in hyperactive plasmacytoid dendritic cells in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) patients are typically presented by their increased serum type I interferon (IFN) activities. Plasmacytoid dendritic cells (pDCs), the most potent type I IFN-producing cells, are found to be hyperactive in SLE. Using the New Zealand Black/White F1 lupus mouse model, we sought for the regulatory mechanism of IFN production by pDCs in SLE. Mice with lupus symptoms such as high titers of serum anti-nuclear antibodies and persistent proteinuria were compared with the pre-symptomatic ones. Upon toll-like receptor (TLR) 7 and TLR9 stimulations, the up-regulations of co-stimulatory markers CD40, CD86 and MHC class II were significantly heightened in bone-marrow-derived pDCs from the symptomatic mice. Furthermore, the expression profiles of over 700 microRNA (miRNAs) in pDCs upon TLR7 activation were analyzed by low-density arrays. Among those, miRNA-155 was the most highly induced and its induction was consistently higher in pDCs from the symptomatic mice. It was previously found in human studies that miRNA-155 regulates type I IFN production by pDCs and itself inversely regulated by the autocrine/paracrine IFN dynamics. Current investigations pursue on the correlation between up-regulated miRNA-155 induction and aberrant pDC functions in SLE using miRNA mimics and inhibitors. Together, our study should reveal miRNA-mediated modulations in pDC abnormalities in SLE.