Abstract
The pathogenesis of intestinal Behçet’s disease (BD) remains poorly understood. Therefore, we aimed to discover and validate biomarkers using proteomics analysis and subsequent functional studies. After two-dimensional electrophoresis, candidate proteins were identified using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS). We validated these results by evaluating the protein levels and their functions in vitro using HT-29 colorectal cancer cells, colon tissues from patients and mice, and murine bone marrow derived macrophages (BMDMs). Of the 30 proteins differentially expressed in intestinal BD tissues, we identified seven using MALDI-TOF/TOF MS. Focusing on galectin-3, we found that TGF-B and IL-10 expression was significantly lower in shLGALS3-transfected cells. Expression of GRP78 and XBP1s and apoptosis rates were all higher in shLGALS3-transfected cells upon the induction of endoplasmic reticulum stress. In response to lipopolysaccharide stimulation, microtubule-associated protein 1 light chain 3B accumulated and lysosomes decreased in these cells. Finally, Salmonella typhimurium infection induced caspase-1 activation and increased IL-1β production, which facilitated activation of the NLRC4 inflammasome, in Lgals3−/− murine BMDMs compared to wild type BMDMs. Our data suggest that galectin-3 may play a protective role in the pathogenesis of intestinal BD via modulation of ER stress, autophagy, and inflammasome activation.
Highlights
Intestinal Behçet’s disease (BD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract; the diagnosis of this disease is typically based on colonoscopic features and clinical manifestations[1]
Among other differential protein levels, we observed significantly lower Gal-3 levels in intestinal BD colon tissues, an interesting observation given that Gal-3 has been reported as an immune response regulator in other chronic inflammatory disorders, including inflammatory bowel disease (IBD)
HT-29 cells, and murine bone marrow derived macrophages (BMDMs), we demonstrated that Gal-3 modulates endoplasmic reticulum (ER) stress, autophagy, and inflammasome activation, which suggests that the Gal-3 protein may play a protective role against intestinal BD
Summary
Intestinal Behçet’s disease (BD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract; the diagnosis of this disease is typically based on colonoscopic features and clinical manifestations[1]. A better understanding of the pathogenesis of intestinal BD would be invaluable Both genetic and environmental factors contribute to inflammatory bowel disease (IBD) etiology. We recently identified several genetic loci (IL17A, IL23R, STAT4, NAALADL2, and YIPF7) associated with susceptibility to intestinal BD12,13, relatively little is known about the disease pathogenesis of intestinal BD, highlighting the need for further study to aid in the diagnosis and treatment of this disease. Because of the limitations of currently available biomarkers, proteomics is gaining popularity for biomarker discovery in IBD These approaches have proven useful for the identification of IBD biomarkers, aiding in diagnosis, measurement of disease activity, and the prediction of treatment response[14,15,16]. For the first time, describes the proteomics approaches as useful techniques for identifying biomarkers associated with intestinal BD and reports a previously undescribed association between the disease and the galectin-3 (Gal-3) protein, suggesting a potential significance of this protein in the pathogenesis of intestinal BD
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