CD147 Targeting by AC-73 Induces Autophagy and Reduces Intestinal Fibrosis Associated with TNBS Chronic Colitis (original) (raw)
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Autophagy in intestinal fibrosis: relevance in inflammatory bowel disease
Frontiers in Pharmacology, 2023
Chronic inflammation is often associated with fibrotic disorders in which an excessive deposition of extracellular matrix is a hallmark. Long-term fibrosis starts with tissue hypofunction and finally ends in organ failure. Intestinal fibrosis is not an exception, and it is a frequent complication of inflammatory bowel disease (IBD). Several studies have confirmed the link between deregulated autophagy and fibrosis and the presence of common prognostic markers; indeed, both up-and downregulation of autophagy are presumed to be implicated in the progression of fibrosis. A better knowledge of the role of autophagy in fibrosis may lead to it becoming a potential target of antifibrotic therapy. In this review we explore novel advances in the field that highlight the relevance of autophagy in fibrosis, and give special focus to fibrosis in IBD patients.
Autophagy stimulation prevents intestinal mucosal inflammation and ameliorates murine colitis
British journal of pharmacology, 2017
A defective autophagy is involved in the pathogenesis of inflammatory disorders such as IBD. Cross talk interactions between autophagy and inflammation have been reported and we analyse the effects of autophagy stimulators on murine colitis. Mice were treated with intrarectal administration of TNBS (3.5 mg/20 g BW) and body weight was measured every day and histological damage score analysed two or four days after treatment. Some mice received trehalose (3% in drinking water three weeks before TNBS administration) or a daily administration of rapamycin (1.25 mg/kg, i.p.), betanin (1g/kg, i.p.) or betanin + 3MA (10mg/kg, i.p.). Mucosal protein levels of p-mTOR, p62, LC3, BCL10, NFκB, IκBα and p-IκBα were determined by WB and mRNA expression of TNFα, IL1β, IL6, IL10, COX2, CCR7, CD11c, iNOS and CD86 by qRT-PCR. An impaired autophagy associated with body weight loss and intestinal damage was detected in the mucosa of TNBS-treated mice. Administration of trehalose, rapamycin or betanin ...
Autophagy Stimulation as a Potential Strategy Against Intestinal Fibrosis
Cells, 2019
We recently observed reduced autophagy in Crohn's disease patients and an anti-inflammatory effect of autophagy stimulation in murine colitis, but both anti-and pro-fibrotic effects are associated with autophagy stimulation in different tissues, and fibrosis is a frequent complication of Crohn's disease. Thus, we analyzed the effects of pharmacological modulation of autophagy in a murine model of intestinal fibrosis and detected that autophagy inhibition aggravates, while autophagy stimulation prevents, fibrosis. These effects are associated with changes in inflammation and in collagen degradation in primary fibroblasts. Thus, pharmacological stimulation of autophagy may be useful against intestinal fibrosis.
The Journal of biological chemistry, 2015
Genome-wide association studies of inflammatory bowel diseases identified susceptible loci containing an autophagy-related gene. However, the role of autophagy in the colon, a major affected area in inflammatory bowel diseases, is not clear. Here, we show that colonic epithelial cell-specific autophagy-related gene 7 (Atg7) conditional knock-out (cKO) mice showed exacerbation of experimental colitis with more abundant bacterial invasion into the colonic epithelium. Quantitative PCR analysis revealed that cKO mice had abnormal microflora with an increase of some genera. Consistently, expression of antimicrobial or antiparasitic peptides such as angiogenin-4, Relmβ, intelectin-1, and intelectin-2 as well as that of their inducer cytokines was significantly reduced in the cKO mice. Furthermore, secretion of colonic mucins that function as a mucosal barrier against bacterial invasion was also significantly diminished in cKO mice. Taken together, our results indicate that autophagy in co...
Clinical and Experimental Gastroenterology, 2022
Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active). Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways. Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed. Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice
Journal of Crohn's and Colitis
Background and Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. Methods: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knockout [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. Results: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis.
Journal of immunology (Baltimore, Md. : 1950), 2017
The basis of the increased risk for Crohn's disease conferred by the Atg16L1T300A polymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normal Atg16L1 allele in heterozygous mice. Therefore, we evaluated the function of the Atg16L1T300A polymorphism heterozygote and homozygote in knock-in (KI) mice. Surprisingly, we found that macrophages from both types of KI mice exhibit defective autophagic induction; accordingly, both types of mice exhibit defects in bacterial clearance coupled with increased inflammasome cytokine (IL-1β) responses. Furthermore, macrophages...
Pharmaceuticals
Ulcerative colitis is a chronic and incurable form of inflammatory bowel disease that can increase the risk of colitis-associated cancer and mortality. Limited treatment options are available for this condition, and the existing ones often come with non-tolerable adverse effects. This study is the first to examine the potential benefits of consuming (R,R)-BD-AcAc2, a type of ketone ester (KE), and intermittent fasting in treating chronic colitis induced by dextran sodium sulfate (DSS) in rats. We selected both protocols to enhance the levels of β-hydroxybutyrate, mimicking a state of nutritional ketosis and early ketosis, respectively. Our findings revealed that only the former protocol, consuming the KE, improved disease activity and the macroscopic and microscopic features of the colon while reducing inflammation scores. Additionally, the KE counteracted the DSS-induced decrease in the percentage of weight change, reduced the colonic weight-to-length ratio, and increased the survi...
Autophagy: roles in intestinal mucosal homeostasis and inflammation
Journal of Biomedical Science, 2019
The intestinal mucosa is a site of multiple stressors and forms the barrier between the internal and external environment. In the intestine, a complex interplay between the microbiota, epithelial barrier and the local immune system maintains homeostasis and promotes a healthy gut. One of the major cellular catabolic processes that regulate this homeostasis is autophagy. Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response. Dysregulation of the autophagy process causes disruption of several aspects of the intestinal epithelium and the immune system that can lead to an inappropriate immune response and subsequent inflammation. Genome-wide association studies have found an association between several risk loci in autophagy genes and inflammatory bowel disease. The aim of the current review is to provide an update on the role of autophagy in intestinal mucosal physiology and in the control of inappropriate inflammation.