Andrew Wang, Anna-Marie Fairhurst, Kui Liu, Benjamin Wakeland, Spencer Barnes, Venkat S Malladi, Kasthuribai Viswanathan, Carlos Arana, Igor Dozmorov, Amrita Singhar, Yong Du, Marjaan Imam, Angela Moses, Christian Chen, Ashwini Sunkavalli, Jose Casco, Dinesh Rakheja, Quan-Zhen Li, Chandra Mohan, Carol Clayberger, Edward K Wakeland, Shaheen Khan
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引用次数: 0
Abstract
Although significant progress has been achieved in elucidating the genetic architecture of systemic lupus erythematosus (SLE), identifying genes underlying the pathogenesis has been challenging. The NZM2410-derived lupus susceptibility Sle3 locus is associated with T cell hyperactivity and activated myeloid cells. However, candidate genes associated with these phenotypes have not been identified. Here, we narrow the Sle3 locus to a smaller genomic segment (Sle3k) and show that mice carrying Sle3k and Sle1 loci developed lupus nephritis. We identify Klf13 as the primary candidate gene that is associated with genome-wide transcription changes resulting in higher levels of proinflammatory cytokines, enhanced T cell activation, and hyperresponsiveness of myeloid cells. Correspondingly, Klf13 -/- mice display repression of genes involved in mediating immune activation, including key proinflammatory cytokines/chemokines in T cells and dysregulation in cytokine signaling pathways in myeloid cells in response to toll receptor ligands. Klf13 upregulation is associated with increased production of RANTES, a key chemokine in lupus nephritis, in activated T cells and the kidneys of lupus-prone mice. In sum, our findings reveal Klf13 as a key gene in the Sle3 interval in mediating lupus pathogenesis that may have implications in the rational design of new therapies for SLE.
期刊介绍:
Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.