摘要
Background:Intestinal fibrosis is a common complication in inflammatory bowel disease(IBD),which still lacks of reliable markers and therapeutic options.Cellular senescence has been considered an important mechanism of intestinal fibrosis,but the underlying molecular link remains elusive.Methods:Tissues were stained usingα-smooth muscle actin(α-SMA),fibronectin,and collagen I as markers of myofibroblastic differ-entiation.Cellular senescence was confirmed through Lamin B1 staining,senescence-associatedβ-galactosidase staining,and the expression of senescence-associated secretory phenotype(SASP)factors.We explored the relationship between senescence of intes-tinal epithelial cells(IECs)and intestinal fibrosis,as well as the molecular mechanism underlying this interaction.The effects of irisin on cellular senescence and fibrosis were determined.Results:Here,we identify engulfment and cell motility protein 1(ELMO1)as a novel biomarker for intestinal cellular senescence and fibrosis.In fibrostrictured tissues from patients and murine models with IBD,significantly high levels of cellular senescence score and factors were noted,which positively correlated with the fibrotic regulator fibronectin.Senescent IECs,not fibroblast itself,re-leased SASP factors to regulate fibroblast activation.Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression,which dampened SIRT1 deacetylase activity,enhanced NF-κB(p65)acetylation,and thereby accelerated cellular senes-cence.Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis.Furthermore,irisin,inhibiting the degradation of ELMO1,could downregulate p65 acetylation,reduce IECs senescence,and prevent incipient intestinal fi-brosis in murine colitis models.Conclusions:This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis,and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.
基金
supported by the National Natural Science Foundation of China[81970482 and 82172561]
the Natural Science Foundation of Guangdong[2019A1515011313]
the Guangdong Special Young Talent Plan of Scientific and Technological Innovation[2022B1515020022]
the Complete Peeriod Talent Project of the Sixth Affiliated Hospital[R20210217202501976]
the program of Guangdong Provincial Clinical Research Center for Digestive Diseases[2020B1111170004]
the Guangzhou Science and Technology Plan Project[202201011160]
the National Key Clinical Discipline.
