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

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 <sup>-/-</sup> 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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Journal
Communications Biology
Published
2024-11-06
DOI
https://doi.org/10.1038/s42003-024-07099-0
Citations
3
Primary Topic
Kruppel-like factors research
Type
article
Field-Weighted Citation Impact
0.70

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article

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

Kasthuribai Viswanathan, Venkat S. Malladi, Edward K. Wakeland, Jose Casco et al.
3 citations
Communications Biology
Kruppel-like factors research
0.70
article

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

Kasthuribai Viswanathan, Venkat S. Malladi, Edward K. Wakeland, Jose Casco, Dinesh Rakheja, Marjaan Imam, Carol Clayberger, Chandra Mohan, Igor Dozmorov, Angela Moses, Christian Chen, Anna‐Marie Fairhurst, Ashwini Sunkavalli, Shaheen Khan, Quan‐Zhen Li, Spencer Barnes, Kui Liu, Andrew Wang, Yong Du, Carlos Arana, Benjamin Wakeland, Amrita Singhar
article en
3 citations

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 <sup>-/-</sup> 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.

Communications BiologyVol. 7(1)
Northwestern University (US), Albert Einstein College of Medicine (US), Singapore Immunology Network (SG), Yale University (US), University of Houston (US), The University of Texas Southwestern Medical Center (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, University of Texas Southwestern Medical Center
Zero hunger
Openalex Percentile: Top 29%
Kruppel-like factors research
0.70
DOIOpen Access PDFOpenAlex
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