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Theranostics 2021; 11(16):7797-7812. doi:10.7150/thno.62256 This issue Cite

Research Paper

Twist1 contributes to developing and sustaining corticosteroid resistance in ulcerative colitis

Changqin Liu^1*, Li-Hua Mo^2,3*, Bai-Sui Feng^4*, Qiao-Ruo Jin^2,3, Yan Li⁴, Jianli Lin^2,3, Qing Shu⁵, Zhi-Gang Liu^2,3, Zhanju Liu^1✉, Xiaomin Sun^1✉, Ping-Chang Yang^2,3✉

1. Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
2. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China.
3. Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
4. Department of Gastroenterology, the Second Hospital, Zhengzhou University, Zhengzhou, China.
5. Department of Gastroenterology, First Affiliated Hospital, Shenzhen University, Shenzhen, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Dr. Xiaomin Sun, Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China. E-mail: sxmglclycom; Dr. Ping-Chang Yang. Room A7-509, Lihu Campus, Shenzhen University School of Medicine, 1066 Xueyuan Blvd, Shenzhen 518055, China. E-mail: pcy2356com. Tel: 8675586172722. Fax: 8675586671906. Dr. Zhanju Liu, Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China. E-mail: liuzhanju88com. More

Abstract

Rationale: Corticosteroid resistance (CR) is a serious drawback to steroid therapy in patients with ulcerative colitis (UC); the underlying mechanism is incompletely understood. Twist1 protein (TW1) is an apoptosis inhibitor and has immune regulatory functions. This study aims to elucidate the roles of TW1 in inducing and sustaining the CR status in UC.

Methods: Surgically removed colon tissues of patients with ulcerative colitis (UC) were collected, from which neutrophils were isolated by flow cytometry. The inflammation-related gene activities in neutrophils were analyzed by RNA sequencing. A CR colitis mouse model was developed with the dextran sulfate sodium approach in a hypoxia environment.

Results: Higher TW1 gene expression was detected in neutrophils isolated from the colon tissues of UC patients with CR and the CR mouse colon tissues. TW1 physically interacted with glucocorticoid receptor (GR)α in CR neutrophils that prevented GRα from interacting with steroids; which consequently abrogated the effects of steroids on regulating the cellular activities of neutrophils. STAT3 (Signal Transducer and Activator of Transcription-3) interacted with Ras protein activator like 1 to sustain the high TW1 expression in colon mucosal neutrophils of CR patients and CR mice. Inhibition of TW1 restored the sensitivity to corticosteroid of neutrophils in the colon tissues of a CR murine model.

Conclusions: UC patients at CR status showed high TW1 expression in neutrophils. TW1 prevented steroids from regulating neutrophil activities. Inhibition of TW1 restored the sensitivity to corticosteroids in the colon tissues at the CR status.

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