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DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease

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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.

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Abbreviations

IBD:

Inflammatory bowel disease

CD:

Crohn’s disease

UC:

Ulcerative colitis

DRAM1:

DNA damage-regulated autophagy modulator 1

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

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Funding

This study was funded by the National Natural Science Foundation of China (Grant Nos. 81630018, 82000519, and 81970483).

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Author notes

  1. Yu Zhang, Xiaozhi Li, and Yaoting Li contributed equally.

  2. Minhu Chen and Ren Mao contributed equally.

Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan II Road, Guangzhou, 510080, People’s Republic of China

    Yu Zhang, Xiaozhi Li, Yaoting Li, Ying Li, Ying Wang, Liguo Zhu, Peng Chen, Zhenyi Tian, Yun Qiu, Rui Feng, Zhirong Zeng, Yao He, Baili Chen, Shenghong Zhang, Ren Mao & Minhu Chen

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  1. Yu Zhang
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Correspondence to Minhu Chen.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international and national guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the First Affiliated Hospital of Sun Yat-sen University ([2018]038).

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Zhang, Y., Li, X., Li, Y. et al. DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease. Dig Dis Sci 66, 3375–3390 (2021). https://doi.org/10.1007/s10620-020-06697-2

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