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

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.

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

“…The inhibition of HtrA2 by the serine protease UCF-101 alleviates DSS-induced colitis by preventing the necroptosis of intestinal epithelial cells [ 103 ]. Furthermore, an unexpected connection between necroptosis and the members of the disintegrin and metalloproteinase (ADAM) protease family is also described [ 104 ].…”

“…Necrostatins are tryptophan-based compounds that inhibit the kinase activity of RIPK1 [ 134 , 135 ]. Nec-1 significantly decreases intestinal inflammation in vitro and in cultured intestinal explants from IBD [ 102 ] and reduces colitis-associated tumorigenesis in mice [ 103 ]. Nec-1 and the stable modified form, nec-1s, prevent necroptosis, although with moderate potency and poor pharmacokinetic properties [ 134 , 135 ].…”

Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

“…7 UCF101 could suppress necroptosis by preventing HtrA2 from degrading RIPK1. 30 Our study, however, focused on the diverse mechanisms of VDR in protecting against colitis. The protective role of the vitamin D signaling pathway in IBD has been demonstrated in numerous studies, but the mechanisms are far from fully understood.…”

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

“…Dextran sodium sulphate (DSS) which is used as a common model of colitis and irritable bowel has marked effects upon intestinal integrity and microbial constituents. DSS is known to particularly damage epithelial cells of the intestine and promote a leaky mucosal barrier [291]. The DSS treated mice lose weight and display marked infiltration and activation of inflammatory neutrophils, macrophages, T lymphocytes and other immune cells, together with elevations in circulating inflammatory cytokines, including IL-6 [291,292].…”

“…DSS is known to particularly damage epithelial cells of the intestine and promote a leaky mucosal barrier [291]. The DSS treated mice lose weight and display marked infiltration and activation of inflammatory neutrophils, macrophages, T lymphocytes and other immune cells, together with elevations in circulating inflammatory cytokines, including IL-6 [291,292]. There is also an overall shift in the quantity and diversity of the microbiota species, with DSS destabilizing the microbiota [293].…”