The roles of Interferon Regulatory Factor 5 and Interleukin-1 Receptor-Associated Kinase 4 in systematic lupus erythematosus pathogenesis
Horne, Barry Kevin
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Systemic Lupus Erythematosus (SLE) is a polygenic autoimmune disease. Genome Wide Association Studies (GWAS) have identified Interferon Regulatory Factor 5 (IRF5) and Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as risk loci, however prior research has failed to determine the specific cell types responsible for their roles in SLE pathogenesis or to place them in the same signaling pathway. IRF5 is expressed in the cytoplasm of immune, muscle, fat, and liver cells. Phosphorylation of the IRF5 protein causes activation and translocation to the nucleus, where it acts as a transcription factor. Systemic knockout of IRF5 prevents development of SLE in multiple mouse models. IRAK4 is also expressed in immune cells, where it acts as both a kinase and a scaffolding protein. We hypothesized that the kinase activity of IRAK4 is required in IRF5 activating pathways in immune cells during SLE pathogenesis. To test this, we conducted mouse bone marrow (BM) chimera studies involving the transfer of SLE-prone FcγRIIB-/-Yaa or SLE-protected FcγRIIB-/-.IRF5-/-Yaa BM cells to B6.SJL-Ptprca Pepcb/BoyJ (“CD45.1”) mice that do not develop SLE. Recipients were then examined for typical SLE markers: autoantibodies, adenopathy, splenomegaly, weight loss, and renal disease. Transfer of BM progenitors from the SLE-prone mice led to SLE in the recipients within 2-3 months of transplantation and the phenotype required IRF5 expression. Isolating and transducing BM stem cells from the SLE-protected group with a retroviral construct before transplantation established that replacement of the IRF5 gene was sufficient to restore the SLE phenotype, even when the number of cells expressing the transgene was low (<10%). Analysis of these transgene chimeras also yielded new insights on cell specific IRF5 aspects of the disease and phenotype marker interdependencies. Separately, we crossed FcγRIIB-/-Yaa mice with a line in which IRAK4 was modified to eliminate its kinase activity without altering its structural scaffold function. These hybrids demonstrated that IRAK4 kinase activity is required for the development of SLE and the phosphorylation of IRF5 in B cells stimulated with a Toll-like receptor 7 (TLR-7) ligand. Our combined results demonstrate that both IRAK4 kinase activity and IRF5 are required in immune cells for the development of SLE.
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