DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in In
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ORIGINAL ARTICLE
DNA Damage‑Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease Yu Zhang1 · Xiaozhi Li1 · Yaoting Li1 · Ying Li1 · Ying Wang1 · Liguo Zhu1 · Peng Chen1 · Zhenyi Tian1 · Yun Qiu1 · Rui Feng1 · Zhirong Zeng1 · Yao He1 · Baili Chen1 · Shenghong Zhang1 · Ren Mao1 · Minhu Chen1 Received: 17 March 2020 / Accepted: 24 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background and Aims DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. Methods DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. Results DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn’s disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. Conclusions During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage. Keywords Inflammatory bowel disease · DRAM1 · Autophagy · Apoptosis · Intestinal inflammation · JNK Abbreviations IBD Inflammatory bowel disease CD Crohn’s disease UC Ulcerative colitis DRAM1 DNA damage-regulated autophagy modulator 1 Yu Zhang, Xiaozhi Li, and Yaoting Li contributed equally. Minhu Chen and Ren Mao contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10620-020-06697-2) contains supplementary material, which is available to authorized users.
CRP C-reactive protein ESR Erythrocyte sedimentation rate SES-CD Simple endoscopic score for Crohn’s disease scoring system Mayo UC Mayo clinic endoscopic subscore system AAV-DRAM1-KD Adeno-associated virus (AAV)mediated DRAM1 knockdown TNBS Trinitrobenzene sulfonic acid DSS Dextran sulfate sodium JNK c-Jun N-terminal kinase
* Minhu Chen [email protected] Extended author information available on the last page of the article
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