Barrier In Inflammatory Bowel Disease Research Articles

Inhibition of Immunoproteasome Attenuates NLRP3 Inflammasome Response by Regulating E3 Ubiquitin Ligase TRIM31

Excessive secretion of pro-inflammatory cytokines leads to the disruption of intestinal barrier in inflammatory bowel disease (IBD). The inflammatory cytokine tumor necrosis factor alpha (TNFα) induces the assembly of the NLRP3 inflammasome, resulting in the augmented secretion of inflammatory cytokines implicated in the pathogenesis of inflammatory bowel disease (IBD). TNFα has also been known to induce the formation of immunoproteasome (IP), which incorporates immunosubunits LMP2, LMP7, and MECL-1. Inhibition of IP activity using the IP subunit LMP2-specific inhibitor YU102, a peptide epoxyketone, decreased the protein levels of NLRP3 and increased the K48-linked polyubiquitination levels of NLRP3 in TNFα-stimulated intestinal epithelial cells. We observed that inhibition of IP activity caused an increase in the protein level of the ubiquitin E3 ligase, tripartite motif-containing protein 31 (TRIM31). TRIM31 facilitated K48-linked polyubiquitination and proteasomal degradation of NLRP3 with an enhanced interaction between NLRP3 and TRIM31 in intestinal epithelial cells. In addition, IP inhibition using YU102 ameliorated the symptoms of colitis in the model mice inflicted with dextran sodium sulfate (DSS). Administration of YU102 in the DSS-treated colitis model mice caused suppression of the NLRP3 protein levels and accompanied inflammatory cytokine release in the intestinal epithelium. Taken together, we demonstrated that inhibiting IP under inflammatory conditions induces E3 ligase TRIM31-mediated NLRP3 degradation, leading to attenuation of the NLRP3 inflammatory response that triggers disruption of intestinal barrier.

Procyanidin C1 Modulates the Microbiome to Increase FOXO1 Signaling and Valeric Acid Levels to Protect the Mucosal Barrier in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) refers to a pair of prevalent conditions (Crohn’s disease and ulcerative colitis) distinguished by persistent inflammation of the large intestine. Procyanidin C1 (PCC1) is a naturally occurring substance derived from grape seeds that has demonstrated notable anti-inflammatory properties. This study examines the potential utility of PCC1 as a treatment for IBD and subsequently examines the host-cell- and microbiome-related mechanisms underlying the detected therapeutic benefits. Working with a classic dextran sodium sulfate (DSS)-induced mouse IBD model, we show that PCC1 protects the mucosal barrier and thereby confers strong protective effects against IBD. PCC1 pretreatment resulted in anti-inflammatory effects and protection against multiple pathological phenotypes in the IBD model mice, including reduced weight loss, lower Disease Activity Index (DAI) totals, and enhanced colon size, as well as obviously beneficial effects on the mucosal barrier (e.g., barrier thickness and activity of mucus-degrading enzymes). We also analyzed the autophagy marker LC3 and found that the level of LC3 was significantly elevated in the intestinal epithelial cell samples of the PCC1-pretreatment group as compared with the non-model mice samples. PCC1 altered the fecal microbiome composition, which included elevating the abundance of Akkermansia muciniphila and Christensenella minuta. Fecal microbiome transplant (FMT) experiments showed that delivering a microbiome from PCC1-treated animals into PCC1-naïve animals conferred protection. Metabolic profiling revealed that both the PCC1-pretreatment and PCC1 FMT groups had elevated levels of the microbiota-derived metabolite valeric acid, and supplementation with this short-chain fatty acid (SCFA) also conferred strong protection against IBD. Finally, inhibitor experiments confirmed that the beneficial effects of valeric acid on the mucus layer are mediated by FOXO1 signaling in the goblet cells of the intestinal epithelium. Beyond showing that PCC1 confers anti-inflammatory effects and protection against IBD by altering the microbiome, our study demonstrates proof of principle for multiple straightforward interventions (PCC1, FMT, and valeric acid supplementation) for ameliorating mucosal barrier damage to treat IBD.

Intestinal barrier in inflammatory bowel disease: A bibliometric analysis.

The primary objective of this investigation was to examine the evolving trajectories and pivotal focal points within the domain of research on intestinal barriers with regard to inflammatory bowel disease (IBD). Publications germane to the intestinal barrier in the context of IBD were procured from the Science Citation Index Expanded within the Web of Science Core Collection database. Bibliometric scrutiny and visualization were executed employing the R package "bibliometrix" through the R software platform (version: 4.3.0). A comprehensive compilation of 7344 English-language articles spanning from January 1, 2001 to December 31, 2021 was meticulously identified and included in the analysis. Remarkably, China emerged as the preeminent force in the realm of intestinal barrier research in relation to IBD. The significance of the intestinal barrier in the context of IBD has been progressively and comprehensively acknowledged. This recognition has ushered in a fresh therapeutic perspective that offers the promise of enhancing the management of inflammation and prognostication.

The interplay between the microbiota, diet and T regulatory cells in the preservation of the gut barrier in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is becoming more common in the Western world due to changes in diet-related microbial dysbiosis, genetics and lifestyle. Incidences of gut permeability can predate IBD and continued gut barrier disruptions increase the exposure of bacterial antigens to the immune system thereby perpetuating chronic inflammation. Currently, most of the approved IBD therapies target individual pro-inflammatory cytokines and pathways. However, they fail in approximately 50% of patients due to their inability to overcome the redundant pro inflammatory immune responses. There is increasing interest in the therapeutic potential of T regulatory cells (Tregs) in inflammatory conditions due to their widespread capability to dampen inflammation, promote tolerance of intestinal bacteria, facilitate healing of the mucosal barrier and ability to be engineered for more targeted therapy. Intestinal Treg populations are inherently shaped by dietary molecules and gut microbiota-derived metabolites. Thus, understanding how these molecules influence Treg-mediated preservation of the intestinal barrier will provide insights into immune tolerance-mediated mucosal homeostasis. This review comprehensively explores the interplay between diet, gut microbiota, and immune system in influencing the intestinal barrier function to attenuate the progression of colitis.

Intestinal barrier in inflammatory bowel disease: A bibliometric and knowledge-map analysis.

Barrier surfaces composed of specialized epithelial cells separate the host body from the external environment, and are essential for maintaining proper intestinal physiologic and immune homeostasis. To explore the development trends and research hotspots of intestinal barrier research in inflammatory bowel disease (IBD). The publications related to the intestinal barrier in IBD were obtained from the Web of Science Core Collection database. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace and R software. A total of 4482 articles published between 2002 and 2022 were identified. The United States is dominant in intestinal barrier research, whereas the University of Chicago is the most active institution. Jerrold from Harvard Medical School was the most productive authors with the most citations. The journals Inflammatory Bowel Disease and Gastroenterology have made significant contributions in this field. The keywords appearing at high frequency related to the intestinal barrier in IBD were detected, including nuclear factor kappa B, tumor necrosis factor-α, apoptosis, oxidative stress and probiotics. Among them, antioxidants, Akkermansia muciniphila, nanoparticles, short-chain fatty acids and extracellular vesicles have received growing interest in recent research. The intestinal barrier field is developing rapidly with extensive cooperation. Targeting the gut microbiota and dietary metabolism to regulate the intestinal barrier has shown promising prospective applications and has generated broad interest. The importance of the intestinal barrier in IBD is gradually being fully recognized, providing a new therapeutic perspective for improving inflammation and prognosis.

Effects of hydroxychloroquine on intestinal mucosal barrier and gut microbiota in inflammatory-bowel disease of mice

Hydroxychloroquine (HCQ) effect on gut microbiota and intestinal mucosal barrier in Inflammatory-Bowel Disease (IBD) was evaluated in this work. Here, we established an IBD model before treating mice with HCQ. After HCQ treatment, the body weight, colon length and fecal occult blood of mice did not change significantly.

Autotaxin (ATX) inhibits autophagy leading to exaggerated disruption of intestinal epithelial barrier in colitis

Inflammatory bowel disease (IBD) is an immune-mediated disease. Autotaxin (ATX) is associated with increased inflammatory molecules, however, its effect on IBD is not well understood. Autophagy plays an important role in IBD, whether ATX and autophagy act in concert in IBD remains unknown. This study is to explore the possible mechanisms of ATX affecting autophagy leading to the disruption of intestinal epithelial barrier, thereby exacerbating colitis. The expression of ATX was upregulated in UC patients and dextran sulfate sodium (DSS)-induced colitis mice. Here, we described that providing an ATX inhibitor during DSS colitis increased autophagy and ameliorated colonic inflammation. Conversely, intrarectal administration with recombinant (r)ATX increased colitis and decreased autophagy. This pro-colitic effect was attenuated in mice treated with rapamycin, resulting in increased autophagy activity and mild colitis. Moreover, the inhibitory effect of rATX on autophagy was confirmed in vitro and was reversed by the addition of rapamycin. The damaging effects of ATX on epithelial barrier function were reversed by ATX inhibitor or rapamycin treatment. In sum, our results show that ATX can inhibit autophagy through the mTOR pathway, resulting in exaggerated damage to the intestinal epithelial barrier during colitis. These findings suggest that ATX may be a key pro-colitic factor, and represent a potential therapeutic target for treating IBD in the future.

Postbiotic muramyl dipeptide alleviates colitis via activating autophagy in intestinal epithelial cells.

The pathogenesis of IBD is complicated and still unclear. Nucleotide-binding oligomerization domain 2 (NOD2) plays a significant role in regulating gut inflammation under the activation of muramyl dipeptide (MDP), which is used as a postbiotic. The study aimed to investigate the effect of MDP on the intestinal barrier in colitis and the mechanism involved. In this study, C57BL/6 mice were challenged with dextran sodium sulfate (DSS) for establishing a colitis model with the pre-treatment of MDP in vivo. Intestinal permeability was reflected by detecting the serum concentration of 4kDa Fluorescein Isothiocyanate-Dextran. The expression of inflammation, barrier-related proteins, and autophagy was tested by Western Blotting. Proliferation and apoptosis in intestinal epithelial cells were detected by immunohistochemistry. Caco-2 cells were exposed to lipopolysaccharide for imitating inflammation in vitro. The findings showed that administration of MDP ameliorated losses of body weight loss, gross injury, and histology score of the colon in the DSS-induced colitis mice. MDP significantly ameliorated the condition of gut permeability, and promoted intestinal barrier repair by increasing the expression of Zonula occludens-1 and E-cadherin. Meanwhile, MDP promoted proliferation and reduced apoptosis of intestinal epithelial cells. In the experiment group treated with MDP, LC3 was upregulated, and p62 was downregulated, respectively. These results suggested that MDP stimulation attenuates intestinal inflammation both in vivo and in vitro. Potentially, MDP reduced the intestinal barrier damage by regulating autophagy in intestinal epithelial cells. Future trials investigating the effects of MDP-based postbiotics on IBD may be promising.

Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis

Background and aimsDiscoidin domain receptor 1 (DDR1) encodes a receptor tyrosine kinase involved in multiple physiological and pathological processes. DDR1 is expressed in the intestinal epithelium, but its role in Ulcerative Colitis (UC) is poorly understand. This study aimed to identify the function of DDR1 in maintaining the homeostasis of UC. MethodsThe DDR1 expression level in non-inflamed and inflamed colon samples from IBD patients were assessed. DDR1 knock-out (DDR1-/-) and wild-type (WT) mice were administered dextran sulfate sodium (DSS) to induce colitis and assessed based on colitis symptoms. In addition, intestinal epithelial barrier injury was induced by TNF-α and IFN-γ incubation to cell monolayers transfected with PCDH-DDR1 or pLKO.1-sh-DDR1–1 plasmids. The effect of DDR1 in regulating barrier integrity, tight junctions (TJ) protein status, and cell apoptosis was investigated in vivo and in vitro. Furthermore, the activation of the NF-κB p65-MLCK-p-MLC2 pathway was also investigated. ResultsDecreased DDR1 expression levels were observed at the inflamed sites compared with the non-inflamed. DDR1-/- mice had alleviated intestinal mucosal barrier injuries, upregulated TJ proteins, decreased epithelium apoptosis from DSS-induced colitis, and reduced proinflammatory cytokines production in the colon. These findings were further confirmed in vitro. DDR1 over-expression aggravated the TNF-α/IFN-γ-induced TJ disruption, while DDR1 shRNA prevented TJ damage even in the presence of JSH-23. DDR1 dependently destroyed the intestinal barrier via the NF-κB p65-MLCK-p-MLC2 pathway. ConclusionOur findings revealed that DDR1 regulated the intestinal barrier in colitis by modulating TJ proteins expression and epithelium apoptosis, making it a potential target of UC.

Ischemic Heart Disease in Patients with Inflammatory Bowel Disease: Risk Factors, Mechanisms and Prevention

According to new research, a possible association between inflammatory bowel disease (IBD) and an increased risk of ischemic heart disease (IHD) has been demonstrated, but this concern is still debatable. The purpose of this review is to investigate the link between IHD and IBD, as well as identify further research pathways that could help develop clinical recommendations for the management of IHD risk in IBD patients. There is growing evidence suggesting that disruption of the intestinal mucosal barrier in IBD is associated with the translocation of microbial lipopolysaccharides (LPS) and other endotoxins into the bloodstream, which might induce a pro-inflammatory cytokines response that can lead to endothelial dysfunction, atherosclerosis and acute cardiovascular events. Therefore, it is considered that the long-term inflammation process in IBD patients, similar to other chronic inflammatory diseases, may lead to IHD risk. The main cardiovascular risk factors, including high blood pressure, dyslipidemia, diabetes, smoking, and obesity, should be checked in all patients with IBD, and followed by strategies to reduce and manage early aggression. IBD activity is an important risk factor for acute cardiovascular events, and optimizing therapy for IBD patients should be followed as recommended in current guidelines, especially during active flares. Large long-term prospective studies, new biomarkers and scores are warranted to an optimal management of IHD risk in IBD patients.

MiRNAs Can Affect Intestinal Epithelial Barrier in Inflammatory Bowel Disease.

The most obvious pathological characterization of inflammatory bowel disease (IBD) is intestinal epithelium erosion and severe inflammation invasion. Micro-ribonucleic acids (miRNA or microRNA), single-stranded noncoding RNAs of ~22 nucleotides, have been considered as the potential therapeutic targets in the pathogenesis of IBD. Many previous studies have focused on the mechanisms that miRNAs use to regulate inflammation, immunity, and microorganisms in IBD. The review highlights in detail the findings of miRNAs in the intestinal epithelial barrier of IBD, and focuses on their gene targets, signaling pathways associated with IBD, and some potential therapies. It will be beneficial for the elucidation of the interaction between miRNAs and the intestinal epithelial barrier in IBD and provide a theoretical reference for preventing and treating IBD in the future.

Interaction Between Commensal Bacteria, Immune Response and the Intestinal Barrier in Inflammatory Bowel Disease.

In inflammatory bowel disease (IBD), intestinal mucosa cell and intestinal epithelial cell are severely damaged, and then their susceptibility to bacteria increases, so many commensal bacteria become pathogenic. The pathogenic commensal bacteria can stimulate a series of compensatory immune responses in the intestine. However, the immune response prevents the intestinal tract from restoring homeostasis, which in turn produces an indispensable inflammatory response. On the contrary, in IBD, the fierce inflammatory response contributes to the development of IBD. However, the effect of commensal bacteria on inflammation in IBD has not been clearly studied. Therefore, we further summarize the changes brought about by the changes of commensal bacteria to the inflammation of the intestines and their mutual influence. This article reviews the protective mechanism of commensal bacteria in healthy people and the mechanism of commensal bacteria and immune response to the destruction of the intestinal barrier when IBD occurs. The treatment and prevention of IBD are also briefly summarized.

Gut Microbiota and Dietary Factors as Modulators of the Mucus Layer in Inflammatory Bowel Disease.

The gastrointestinal tract is optimized to efficiently absorb nutrients and provide a competent barrier against a variety of lumen environmental compounds. Different regulatory mechanisms jointly collaborate to maintain intestinal homeostasis, but alterations in these mechanisms lead to a dysfunctional gastrointestinal barrier and are associated to several inflammatory conditions usually found in chronic pathologies such as inflammatory bowel disease (IBD). The gastrointestinal mucus, mostly composed of mucin glycoproteins, covers the epithelium and plays an essential role in digestive and barrier functions. However, its regulation is very dynamic and is still poorly understood. This review presents some aspects concerning the role of mucus in gut health and its alterations in IBD. In addition, the impact of gut microbiota and dietary compounds as environmental factors modulating the mucus layer is addressed. To date, studies have evidenced the impact of the three-way interplay between the microbiome, diet and the mucus layer on the gut barrier, host immune system and IBD. This review emphasizes the need to address current limitations on this topic, especially regarding the design of robust human trials and highlights the potential interest of improving our understanding of the regulation of the intestinal mucus barrier in IBD.

Exploring Effects of Chitosan Oligosaccharides on the DSS-Induced Intestinal Barrier Impairment In Vitro and In Vivo.

Intestinal barrier dysfunction is an essential pathological change in inflammatory bowel disease (IBD). The mucus layer and the intestinal epithelial tight junction act together to maintain barrier integrity. Studies showed that chitosan oligosaccharide (COS) had a positive effect on gut health, effectively protecting the intestinal barrier in IBD. However, these studies usually focused on its impact on the intestinal epithelial tight junction. The influence of COS on the intestinal mucus layer is still poorly understood. In this study, we explored the effect of COS on intestinal mucus in vitro using human colonic mucus-secreted HT-29 cells. COS relieved DSS (dextran sulfate sodium)-induced mucus defects. Additionally, the structural characteristics of COS greatly influenced this activity. Finally, we evaluated the protective effect of COS on intestinal barrier function in mice with DSS-induced colitis. The results indicated that COS could manipulate intestinal mucus production, which likely contributed to its intestinal protective effects.

Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494/EDA2R/\u03b2-catenin signaling in mice

The mucosa microenvironment is critical for intestinal stem cell self-renewal and reconstruction of the epithelial barrier in inflammatory bowel disease (IBD), where the mechanisms underlying cross-talk between intestinal crypts and the microenvironment remain unclear. Here, we firstly identified miR-494-3p as an important protector in colitis. miR-494-3p levels were decreased and negatively correlated with the severity in human IBD samples, as well as in colitis mice. In colitis crypts, a notable cytokine–cytokine receptor, miR-494-3p-targeted EDA2R and the ligand EDA-A2, suppressed colonic stemness and epithelial repair by inhibiting β-catenin/c-Myc. In differentiated IECs, miR-494-3p inhibits macrophage recruitment, M1 activation and EDA-A2 secretion by targeting IKKβ/NF-κB in colitis. A miR-494-3p agomir system notably ameliorated the severity of colonic colitis in vivo. Collectively, our findings uncover a miR-494-3p-mediated cross-talk mechanism by which macrophage-induced intestinal stem cell impairment aggravates intestinal inflammation.

Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases.

The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.

S0862 Increased Prevalence of Dermatitis Herpetiformis Among Patients With IBD Without Concomitant Celiac Disease: Results From a Population-Based Study

INTRODUCTION: Dermatitis herpetiformis (DH) is an autoimmune eruption of pruritic inflammatory papules and vesicles that occur in a grouped arrangement on different parts of the body. It is characterized by granular deposits of immunoglobulin A (IgA) within the dermal papillae on immunofluorescence. Previous case studies (Alonso-Llamazares et al) and case reports have described an association between DH and ulcerative colitis, possibly arising due to an increased permeability of intestinal mucosal barrier in inflammatory bowel disease (IBD) that allows antigen to circulate in the blood and triggering IgA antibodies. Using a large database, we sought to describe the epidemiology and risk of DH in IBD patients. METHODS: We used a commercial database (Explorys Inc, Cleveland, OH), an aggregate of Electronic Health Record data from 26 US healthcare systems. We identified a cohort of patients with IBD, celiac disease and a diagnosis of DH between June 2015 and 2020. Patients were identified based on a Systemized Nomenclature of Medicine Clinical Terms. We calculated the prevalence of DH in patients with IBD, with celiac, general population, and in individuals with neither IBD nor celiac which served as controls. RESULTS: Out of the 39,212,680 patients active from 2015 to 2020, we identified a total of 5,240 patients with DH (0.013%), 280,460 patients with IBD (0.71%), and 115,020 patients with celiac disease (0.29%). Among those with DH, there were 1290 patients diagnosed with celiac disease (without IBD), 120 patients with IBD (without CD), 60 patients with both celiac and IBD, and 3770 patients with neither celiac nor IBD (control group). The prevalence of DH was 1.12% in celiac disease (without IBD) and 0.043% in IBD (without CD). The prevalence of DH among those without celiac nor IBD (in the control group) was 0.0096%. The risk of DH was higher in celiac [OR 116.6 (109.4–124.2)] and in IBD [OR 4.41 (3.68–5.29)] compared to individuals with neither IBD nor celiac. In the cohort with IBD, risk of DH was higher in females compared to males [OR 3.06 (1.77–5.30)], in elderly patients compared to adults aged 18–65 [4.0 (2.34–6.84)], and in Caucasians compared to non-Caucasians (OR 25.0 [12.7–49.3]). CONCLUSION: Using a large population database, we described the epidemiology and risk of DH in IBD patients. We found that the risk of DH is increased in patients with IBD, consistent with prior case series. Further studies are needed to confirm this association and elucidate the mechanism behind this association.Table 1.: Odd’s ratio comparing the prevalence of dermatitis herpetiformis in celiac disease and in IBD to patients with DH without celiac or IBDTable 2.: Gender-, Age- and Race-Based Prevalence of dermatitis herpetiformis in individuals with IBD in the United States between 2015 and 2020

Class A1 scavenger receptors mediated macrophages in impaired intestinal barrier of inflammatory bowel disease.

This study was to investigate the cytokines and phenotype of macrophages pre-treated with class A1 scavenger receptor (SR-A1) antibody in vitro and the influence on apoptotic pathway of colonic epithelial cells, and to explore the role of SR-A1 mediated macrophages in impaired intestinal barrier of inflammatory bowel diseases (IBDs). Mouse macrophage RAW264.7 was pre-treated with SR-A1 antibody in the presence of lipopolysaccharide (LPS). Transwell system was employed for co-culture of RAW264.7 and Caco-2 in the presence of LPS and IFN-γ, with or without SR-A1 antibody pre-treatment. The percentage of F4/80+CD11c+ macrophages, apoptosis rate of Caco-2 cells, and expression of apoptosis and tight junction proteins in Caco-2 cells was determined. Pre-treatment with SR-A1 antibody up-regulated IL-10 expression in RAW264.7, whereas down-regulated the expression of TNF and iNOS. Immunofluorescence staining indicated the upregulation of NF-κB p-p56 after LPS stimulation was significantly inhibited in the presence of SR-A1 antibody. The increase in p-JNK expression was inhibited by SR-A1 antibody. Transwell assay showed the percentage of F4/80+CD11c+ macrophages and apoptotic Caco-2 cells increased after treatment with LPS and IFN-γ, which could be reversed in the presence of SR-A1 antibody. The induction of cleaved caspase-3 and claudin-1 in Caco-2 cells was also suppressed when SR-A1 antibody pre-treatment. Pre-treatment with SR-A1 antibody can inhibit inflammatory response in LPS-induced macrophages in a NF-κB dependent manner. Pre-treatment with SR-A1 antibody also inhibits M1 phenotype expression of macrophages, and attenuates the pro-apoptotic effect on colonic epithelial cells and disruption of intestinal barrier integrity induced by macrophages.

Effects and Mechanism of Constitutive TL1A Expression on Intestinal Mucosal Barrier in DSS-Induced Colitis.

The role of TL1A in the intestinal mucosa barrier in inflammatory bowel disease (IBD) is still unclear. This study was aimed to investigate the expression levels of tight junction protein (TJ), myosin light chain kinase (MLCK), MyD88 and tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF6) and how TL1A influences the intestinal barrier in IBD. The mouse models of IBD were built using FMS-TL1A-GFP-transgenic mice and wild-type mice. The morphological and histopathological changes, bacterial translocation, permeability of colonic mucosa, and LPS level were assessed. Caco-2 cells were used to further investigate the association between TL1A and TNF-α and LPS. The protein level and mRNA changes of TJ proteins including ZO-1, occluding, JAMA, claudin-1, claudin-2, and claudin-3 were investigated using Western blot and real-time PCR. Protein changes of MLCK, MyD88 and TNF receptor-associated factor-6 (TRAF6), and TNF-α mRNA in the mouse colon were further assessed. The IBD models were successfully built. Cooper HS score and histopathological score of the colon were higher in DSS/WT group than in control/WT group (P < 0.05), higher in DSS/Tg group than in control/Tg group (P < 0.05), and higher in DSS/Tg group than in DSS/WT group. PAS, colonic permeability of the colon, and FITC-D examination showed the similar results and trends. Compared with control/WT group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/WT group (P < 0.05). Compared with control/Tg group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/Tg group. Compared with Caco-2 + TNF-α group, the expression level of occludin and claudin-1 in Caco-2 + LV-TNFSF15 + TNF-α group was significantly lower (P < 0.05); p-MLC level was significantly higher. Compared with Caco-2 + LPS group, the expression level of occludin and claudin-1 significantly decreased in Caco-2 + LV-TNFSF15 + LPS group; MyD88 and TRAF6 expression level significantly increased. The results suggested that TL1A could impair intestinal epithelial barrier in the mouse model of IBD and might regulate TJ expression via MLCK/p-MLC pathway and LPS-mediated MyD88/TRAF6 pathway.

HDAC inhibitors promote intestinal epithelial regeneration via autocrine TGFβ1 signalling in inflammation.

Intact epithelial barrier function is pivotal for maintaining intestinal homeostasis. Current therapeutic developments aim at restoring the epithelial barrier in inflammatory boweldisease. Histone deacetylase (HDAC) inhibitors are known to modulate immune responses and to ameliorate experimental colitis. However, their direct impact on epithelial barrier function and intestinal wound healing is unknown. In human and murine colonic epithelial cell lines, the presence of the HDAC inhibitors Givinostat and Vorinostat not only improved transepithelial electrical resistance under inflammatory conditions but also attenuated the passage of macromolecules across the epithelial monolayer. Givinostat treatment mediated an accelerated wound closure in scratch assays. In vivo, Givinostat treatment resulted in improved barrier recovery and epithelial wound healing in dextran sodium sulphate-stressed mice. Mechanistically, these regenerative effects could be linked to an increased secretion of transforming growth factor beta1 and interleukin 8, paralleled by differential expression of the tight junction proteins claudin-1, claudin-2 and occludin. Our data reveal a novel tissue regenerative property of the pan-HDAC inhibitors Givinostat and Vorinostat in intestinal inflammation, which may have beneficial implications by repurposing HDAC inhibitors for therapeutic strategies for inflammatory bowel disease.