New molecular pathways leading to IRF5-mediated SLE
It’s known that systemic lupus erythematosus (SLE) can be partly genetic. Previously, scientists identified that a molecule called interferon regulatory factor 5 (IRF5) contributes to SLE, and people with variants to IRF5 genes have a high risk of developing SLE. IRF5 plays an essential role in regulating the immune system, but it becomes overactivated and causes the immune system to become hyperactive in SLE patients. Researchers have not yet found a way to block IRF5 hyperactivity in humans safely.
Dr. Barnes recently identified a protein called serine/threonine protein kinase 25 (STK25) that turns on IRF5 in SLE immune cells. She will use the LRA Lupus Mechanisms and Targets Award to determine if STK25 is a new therapeutic target for SLE. The researchers will compare STK25 activity in healthy people with and without IRF5 gene variants to STK25 activity in SLE patients and determine how STK25 activates IRF5 in response to SLE triggers. Lupus mice will be used to determine if loss of the STK25 gene protects against lupus disease development and severity.
What this study means for people with lupus
This work is designed to explore if targeting STK25 or IRF5 could offer a new safe and selective therapeutic strategy to prevent and/or treat SLE.
Systemic lupus erythematosus (SLE) is a highly complex and variable autoimmune disease, yet common threads run through it, including loss of self-tolerance, persistent autoantibody production, enhanced type I interferon expression, complement activation, inflammation, and tissue damage. While the drivers of SLE are still obscure, the disorder is highly heritable and genetic variants have been identified that contribute to disease pathogenesis. The transcription factor interferon regulatory factor 5 (IRF5) is an essential mediator of innate and adaptive immunity, and IRF5 genetic variants have the second highest odds ratio for SLE risk after HLA genes. We reported that healthy donors carrying the IRF5-SLE risk haplotype have characteristics of pre-symptomatic SLE, including increased levels of circulating plasma cells, anti-nuclear autoantibodies and spontaneous NETosis, as compared to non-risk carriers. One of the main phenotypes identified in healthy donor risk carriers was constitutive IRF5 nuclear translocation or hyper-activation. Others and we previously reported that IRF5 expression and activation were significantly elevated in immune cells from SLE patients as compared to healthy donors, and mice lacking Irf5, or lupus-prone mice treated with an inhibitor of IRF5 activation, were protected from disease onset and severity. Together, these findings support the premise that IRF5 hyper-activation and the mechanisms that regulate IRF5 activation/nuclear translocation are viable therapeutic targets for the treatment and/or prevention of SLE. In our search for new molecules and mechanisms that regulate IRF5 activity, we identified STK25 as a novel mediator of Toll-like receptor (TLR)-induced IRF5 signaling. TLR7 and TLR9 play a role in the recognition of self RNA and DNA, respectively, that are produced in SLE. Preliminary data show that STK25 is autophosphorylated in SLE PBMCs that is a prerequisite for kinase activity, leading to IRF5 phosphorylation. TLR-induced IRF5 phosphorylation and nuclear translocation were significantly attenuated in PBMCs from Stk25-/- mice. Based on these preliminary findings, we hypothesize that STK25 is a new candidate kinase that drives IRF5 hyper-activation in SLE. The following Specific Aims have been designed to address this hypothesis: 1) Determine whether STK25 phosphorylates and activates IRF5 in response to SLE triggers, 2) Determine STK25 expression and kinase activity in healthy donor risk and non-risk carriers and SLE patients, and 3) Test the hypothesis that loss of Stk25 will protect mice from lupus disease onset and severity. Results from these studies will provide preclinical validation for the therapeutic modulation of STK25 to inhibit IRF5-mediated lupus onset and progression. Further, analysis of STK25 and IRF5 expression/activation in SLE patient samples and correlation with disease activity will enhance our ability to stratify patients for future clinical trials focused on IRF5 inhibition.