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

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 Ly6C^hi 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.