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<p>Ulcerative colitis (UC) is a debilitating, immune-mediated inflammatory disorder of the gastrointestinal (GI) tract with far-reaching consequences on distal organs, including the bone marrow. Here, we describe the molecular mechanisms that contribute to UC-induced abnormal hematopoiesis. We show that chronic UC drives HSPC differentiation toward myelopoiesis in an APE1/Ref-1/HIF-1α/IL-1r1-dependent manner. Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory <i>milieu</i> of UC, including suppression of pro-inflammatory Ly6C<sup>hi</sup> monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop.</p><p></p>

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Ref-1 drives ulcerative colitis induced systemic defects in hematopoietic cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Ramesh Kumar,
  • Rahul Kanumuri,
  • Sarah S. Burns,
  • Baskar Ramdas,
  • Lakshmi Reddy Palam,
  • Santhosh Kumar Pasupuleti,
  • Xuepeng Wang,
  • Rajaraman Eri,
  • Kulmira Nurgali,
  • Mark R. Kelley,
  • Reuben Kapur

摘要

Ulcerative colitis (UC) is a debilitating, immune-mediated inflammatory disorder of the gastrointestinal (GI) tract with far-reaching consequences on distal organs, including the bone marrow. Here, we describe the molecular mechanisms that contribute to UC-induced abnormal hematopoiesis. We show that chronic UC drives HSPC differentiation toward myelopoiesis in an APE1/Ref-1/HIF-1α/IL-1r1-dependent manner. Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory milieu of UC, including suppression of pro-inflammatory Ly6Chi monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop.