Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53

Abstract

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1−/− mice, DJ-1−/−p53−/− mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1−/− mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis

“…Paraffin-embedded sections were subjected to H&E staining for inflammation analysis and Masson’s trichrome staining and Sirius red staining for fibrosis analysis. Inflammation and fibrosis scoring of mouse colon sections was performed as described previously ( 56 ). Briefly, for inflammation analysis, inflammatory cell infiltration was scored as 0 to 3, and tissue damage was scored as 0 to 3.…”

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

“…Moreover, DJ-1 was reported to suppress p53 activity through binding with SIRT1 [85]. Intestinal DJ-1 expression was reduced in patients with inflammatory bowel disease and low DJ-1 expression aggravated p53-mediated intestinal epithelial cell apoptosis in mice with induced colitis [86]. In colorectal cancer, DJ-1 is found to indirectly reduce p53 expression, promoting cancer cell proliferation [87].…”

“…Although preclinical trials with anti-oxidative stress treatments in animals were promising, clinical trials failed to show significant benefit [59]. Yet therapies that increase endogenous antioxidant capacity in heart failure continue to be proposed as future targets [86]. Apart from its role in redox homeostasis, DJ-1 regulates apoptosis and autophagy.…”

Ischemic Postconditioning-Mediated DJ-1 Activation Mitigate Intestinal Mucosa Injury Induced by Myocardial Ischemia Reperfusion in Rats Through Keap1/Nrf2 Pathway

“…Overexpression of DJ-1 can reduce ROS production and alleviate myocardial cell apoptosis by inhibiting PTEN/PI3K/Akt signaling pathway (Xin et al, 2019). Moreover, DJ-1 deficiency significantly aggravated inflammatory bowel disease, evidenced by increased intestinal inflammation and exacerbated intestinal epithelial cell apoptosis (Zhang et al, 2020). si-DJ-1 attenuated the cytoprotective effect of protocatechuic acid on ketoprofen-induced mitochondrial oxidative stress and apoptotic cell death (Cheng et al, 2019).…”