The transcription factor FoxM1 activates Nurr1 to promote intestinal regeneration after ischemia/reperfusion injury

Guo Zu,Jing Guo,Dong Wang,Xiangwen Zhang,Ningwei Che,Baiying Liu,Tingting Zhou

doi:10.1038/s12276-019-0343-y

Abstract

FoxM1 is involved in the regeneration of several organs after injury and expressed in the intestinal mucosa. The intrinsic mechanism of FoxM1 activity in the mucosa after intestinal ischemia/reperfusion (I/R) injury has not been reported. Therefore, we investigated the role of FoxM1 in mediating intestinal mucosa regeneration after I/R injury. Expression of FoxM1 and the proliferation of intestinal mucosa epithelial cells were examined in rats with intestinal I/R injury and an IEC-6 cell hypoxia/reperfusion (H/R) model. The effects of FoxM1 inhibition or activation on intestinal epithelial cell proliferation were measured. FoxM1 expression was consistent with the proliferation of intestinal epithelial cells in the intestinal mucosa after I/R injury. Inhibition of FoxM1 expression led to the downregulation of Ki-67 expression mediated by the inhibited expression of Nurr1, and FoxM1 overexpression promoted IEC-6 cell proliferation after H/R injury through activating Nurr1 expression. Furthermore, FoxM1 directly promoted the transcription of Nurr1 by directly binding the promoter of Nurr1. Further investigation showed low expression levels of FoxM1, Nurr1, and Ki-67 in the intestinal epithelium of patients with intestinal ischemic injury. FoxM1 acts as a critical regulator of intestinal regeneration after I/R injury by directly promoting the transcription of Nurr1. The FoxM1/Nurr1 signaling pathway represents a promising therapeutic target for intestinal I/R injury and related clinical diseases.

Highlights

Intestinal ischemia/reperfusion (I/R) injury is a common pathophysiological process in many clinical settings that includes small bowel transplantation, hemorrhagic shock, and necrotizing enterocolitis[1,2]
To determine the expression of FoxM1 in intestinal mucosa regeneration after I/R injury, we tested the expression of FoxM1 in intestinal tissues that underwent 1 h of ischemia followed by 3, 6, 12, or 24 h of reperfusion
We examined FoxM1 expression in IEC-6 cells in vitro

Summary

Introduction

Intestinal ischemia/reperfusion (I/R) injury is a common pathophysiological process in many clinical settings that includes small bowel transplantation, hemorrhagic shock, and necrotizing enterocolitis[1,2]. It can cause severe intestinal mucosa damage that provokes intestinal mucosal barrier dysfunction. As a typical transcription factor, FoxM1 belongs to the family of Forkhead box (Fox) proteins and is associated with cell proliferation. It is expressed in several embryonic tissues and the testes, thymus and intestinal crypts in adult mice[8,9,10]. Studies have shown that FoxM1 expression is reactivated after organ injury and that

Methods

Results

Conclusion