2. Academic Validation
  3. Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells

Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells

  • Cell Death Dis. 2019 Apr 24;10(5):344. doi: 10.1038/s41419-019-1580-7.
Chong Zhang 1,  Andong He 1,  Shuai Liu 1,  Qiaoling He 1,  Yiqin Luo 1,  Zhilan He 2,  Yujiao Chen 1,  Ailin Tao 3,  Jie Yan 4
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, 510260, Guangzhou, China.
  • 2 The First Affiliated Hospital, Guangdong Pharmaceutical University, 510006, Guangzhou, China.
  • 3 The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, 510260, Guangzhou, China. [email protected].
  • 4 The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, 510260, Guangzhou, China. [email protected].
PMID: 31019191 DOI: 10.1038/s41419-019-1580-7
Abstract

Necroptosis of intestinal epithelial cells has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). The identification of dysregulated proteins that can regulate Necroptosis in dextran sulfate sodium (DSS)-induced colitis is the key to the rational design of therapeutic strategies for colitis. Through tandem mass tag (TMT)-based quantitative proteomics, HtrA2 was found to be downregulated in the colon of DSS-treated mice. UCF-101, a specific serine protease inhibitor of HtrA2, significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss and decreased mortality. UCF-101 decreased DSS-induced colonic inflammation, prevented intestinal barrier function loss and inhibited Necroptosis of intestinal epithelial cells. In vitro, UCF-101 or silencing of HtrA2 decreased Necroptosis of HT-29 and L929 cells. UCF-101 decreased phosphorylation of RIPK1 and subsequent phosphorylation of RIPK3 and MLKL during Necroptosis. Upon necroptotic stimulation, HtrA2 translocated from mitochondria to cytosol. HtrA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of Necroptosis. Our findings highlight the importance of HtrA2 in regulating colitis by modulation of Necroptosis and suggest HtrA2 as an attractive target for anti-colitis treatment.

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