KLF13 promotes SLE pathogenesis by modifying chromatin accessibility of key proinflammatory cytokine genes.

IF 5.2 1区 生物学 Q1 BIOLOGY Communications Biology Pub Date : 2024-11-06 DOI:10.1038/s42003-024-07099-0
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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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.

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KLF13 通过改变关键促炎细胞因子基因的染色质可及性来促进系统性红斑狼疮的发病。
尽管在阐明系统性红斑狼疮(SLE)的遗传结构方面取得了重大进展,但确定其发病机制的基因一直是个挑战。源自 NZM2410 的狼疮易感性 Sle3 基因座与 T 细胞过度活跃和活化的髓样细胞有关。然而,与这些表型相关的候选基因尚未发现。在这里,我们将 Sle3 基因座缩小到一个较小的基因组片段(Sle3k),并证明携带 Sle3k 和 Sle1 基因座的小鼠会患上狼疮肾炎。我们发现 Klf13 是与全基因组转录变化相关的主要候选基因,这种转录变化导致促炎细胞因子水平升高、T 细胞活化增强以及髓系细胞反应性增高。相应地,Klf13 -/-小鼠显示出参与介导免疫激活的基因受到抑制,包括 T 细胞中的关键促炎细胞因子/凝血因子,以及髓系细胞中细胞因子信号通路对收费受体配体反应的失调。Klf13 的上调与活化 T 细胞和狼疮易感小鼠肾脏中狼疮肾炎的关键趋化因子 RANTES 的产生增加有关。总之,我们的发现揭示了 Klf13 是 Sle3 区间介导狼疮发病机制的一个关键基因,这可能对合理设计系统性红斑狼疮的新疗法具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Communications Biology
Communications Biology Medicine-Medicine (miscellaneous)
CiteScore
8.60
自引率
1.70%
发文量
1233
审稿时长
13 weeks
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.
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