Estrogen-dependent microRNAs as potential targets for the treatment of SLE

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease, encompassing a broad spectrum of clinical symptoms ranging from skin/joint manifestations to severely debilitating kidney disease. Given the strong gender imbalance in SLE, a role for estrogen has been indicated. We have uncovered a link between estrogen-regulated microRNAs, their predicted targets, cytokine signatures and the potential that these regulate SLE pathology and progression. For example TRIM21, an E3 ligase important in regulating cytokine production in SLE, is a novel estrogen regulated gene – both at a transcriptional level and by a novel estrogen-regulated microRNA, mir-381. Importantly the use of estrogen receptor antagonists reverses the enhanced production of type I interferons (IFNs) and IL-23 observed in SLE patient monocytes, indicating the potential utility of targeting the estrogen system in SLE treatment. We have identified a panel of estrogen-dependent differentially expressed microRNAs in monocytes whose expression is either up- or down-regulated two fold relative to control. Our analysis to date has shown that a number of these miRs regulate proteins that regulate either immune function, or, target critical signaling proteins that regulate IFN or pro-inflammatory cytokine production. For example, miR-720 targets TRIM56, a positive driver of RIG-I-driven IFN production whereas miR-125a regulates IL-16 expression. Both miRs are down regulated in SLE patient monocytes. We therefore hypothesise that alterations in estrogen-regulated miRNA expression in SLE may contribute to disease pathogenesis through the regulation of key inflammatory pathways.

The overall goal of this program is to characterize how the estrogen system and estrogen regulated microRNAs contributes to cytokine expression and pathology in SLE and how we might exploit our findings to develop microRNA-based therapies for the treatment of SLE. In addition our work aims to contribute to identifying which patients might benefit from estrogen-antagonist therapies.