scholarly journals Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

2019 ◽  
Vol 2 (1) ◽  
pp. e201800229 ◽  
Author(s):  
Claudia Burrello ◽  
Gabriella Pellegrino ◽  
Maria Rita Giuffrè ◽  
Giulia Lovati ◽  
Ilaria Magagna ◽  
...  
Keyword(s):  
Lamina Propria ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Lymphoid Tissues ◽  
Inkt Cells ◽  
Inflammatory Processes ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells’ pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn’s disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients.

scholarly journals Inflammatory Bowel Disease–associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria

2020 ◽  
Vol 26 (12) ◽  
pp. 1856-1868
Author(s):  
Stefanie Derer ◽  
Ann-Kathrin Brethack ◽  
Carlotta Pietsch ◽  
Sebastian T Jendrek ◽  
Thomas Nitzsche ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Mucosal Immune Response ◽  
Disease Manifestation ◽  
Inflammatory Bowel

Abstract Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD’s pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn’s disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD’s pathophysiology.

scholarly journals Development of a human primary gut-on-a-chip to model inflammatory processes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Claudia Beaurivage ◽  
Auste Kanapeckaite ◽  
Cindy Loomans ◽  
Kai S. Erdmann ◽  
Jan Stallen ◽  
...  
Keyword(s):  
Human Colon ◽  
In Vitro Models ◽  
Intestinal Epithelial ◽  
Activated Macrophages ◽  
Polarized Secretion ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Key Aspects

AbstractInflammatory bowel disease (IBD) is a complex multi-factorial disease for which physiologically relevant in vitro models are lacking. Existing models are often a compromise between biological relevance and scalability. Here, we integrated intestinal epithelial cells (IEC) derived from human intestinal organoids with monocyte-derived macrophages, in a gut-on-a-chip platform to model the human intestine and key aspects of IBD. The microfluidic culture of IEC lead to an increased polarization and differentiation state that closely resembled the expression profile of human colon in vivo. Activation of the model resulted in the polarized secretion of CXCL10, IL-8 and CCL-20 by IEC and could efficiently be prevented by TPCA-1 exposure. Importantly, upregulated gene expression by the inflammatory trigger correlated with dysregulated pathways in IBD patients. Finally, integration of activated macrophages offers a first-step towards a multi-factorial amenable IBD platform that could be scaled up to assess compound efficacy at early stages of drug development or in personalized medicine.

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

2020 ◽  
Vol 295 (13) ◽  
pp. 4237-4251 ◽  
Author(s):  
Jie Zhang ◽  
Min Xu ◽  
Weihua Zhou ◽  
Dejian Li ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cell ◽  
Bowel Disease ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
P53 Expression ◽  
Inflammatory Bowel

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.

scholarly journals Ex vivo Ikkβ ablation rescues the immunopotency of mesenchymal stromal cells from diabetics with advanced atherosclerosis

2020 ◽  
Author(s):  
Ozge Kizilay Mancini ◽  
David N Huynh ◽  
Liliane Menard ◽  
Dominique Shum-Tim ◽  
Huy Ong ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Therapeutic Effects ◽  
Atherosclerotic Cardiovascular Disease ◽  
Myocardial Repair ◽  
Iκb Kinase

Abstract Aims Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes mellitus (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency). This is mediated by an inflammatory shift in MSC-secreted soluble factors (i.e. pro-inflammatory secretome) and can contribute to the reduced therapeutic effects of autologous T2DM and atherosclerosis-MSC post-MI. The signalling pathways driving the altered secretome of atherosclerosis- and T2DM-MSC are unknown. Specifically, the effect of IκB kinase β (IKKβ) modulation, a key regulator of inflammatory responses, on the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has not been studied. Methods and results MSCs were isolated from adipose tissue obtained from patients with (i) atherosclerosis and T2DM (atherosclerosis+T2DM MSCs, n = 17) and (ii) atherosclerosis without T2DM (atherosclerosis MSCs, n = 17). MSCs from atherosclerosis+T2DM individuals displayed an inflammatory senescent phenotype and constitutively expressed active forms of effectors of the canonical IKKβ nuclear factor-κB transcription factors inflammatory pathway. Importantly, this constitutive pro-inflammatory IKKβ signature resulted in an altered secretome and impaired in vitro immunopotency and in vivo healing capacity in an acute MI model. Notably, treatment with a selective IKKβ inhibitor or IKKβ knockdown (KD) (clustered regularly interspaced short palindromic repeats/Cas9-mediated IKKβ KD) in atherosclerosis+T2DM MSCs reduced the production of pro-inflammatory secretome, increased survival, and rescued their immunopotency both in vitro and in vivo. Conclusions Constitutively active IKKβ reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome composition. Modulation of IKKβ in atherosclerosis+T2DM MSCs enhances their myocardial repair ability.

scholarly journals UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling

2021 ◽  
Vol 14 (6) ◽  
pp. 502
Author(s):  
Carmine Giorgio ◽  
Marika Allodi ◽  
Simone Palese ◽  
Andrea Grandi ◽  
Massimiliano Tognolini ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Drug Candidate ◽  
Eph Receptors ◽  
Beneficial Effects ◽  
Bidirectional Signaling ◽  
Novel Drug

Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn’s disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.

scholarly journals Capsular polysaccharide correlates with immune response to the human gut microbe Ruminococcus gnavus

2021 ◽  
Vol 118 (20) ◽  
pp. e2007595118
Author(s):  
Matthew T. Henke ◽  
Eric M. Brown ◽  
Chelsi D. Cassilly ◽  
Hera Vlamakis ◽  
Ramnik J. Xavier ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Capsular Polysaccharide ◽  
Inflammatory Responses ◽  
Cell Wall Polysaccharide ◽  
Proinflammatory Responses ◽  
Gut Microbe ◽  
Inflammatory Bowel

Active inflammatory bowel disease (IBD) often coincides with increases of Ruminococcus gnavus, a gut microbe found in nearly everyone. It was not known how, or if, this correlation contributed to disease. We investigated clinical isolates of R. gnavus to identify molecular mechanisms that would link R. gnavus to inflammation. Here, we show that only some isolates of R. gnavus produce a capsular polysaccharide that promotes a tolerogenic immune response, whereas isolates lacking functional capsule biosynthetic genes elicit robust proinflammatory responses in vitro. Germ-free mice colonized with an isolate of R. gnavus lacking a capsule show increased measures of gut inflammation compared to those colonized with an encapsulated isolate in vivo. These observations in the context of our earlier identification of an inflammatory cell-wall polysaccharide reveal how some strains of R. gnavus could drive the inflammatory responses that characterize IBD.

Immunomodulatory Effects of Flavonoids in the Prophylaxis and Treatment of Inflammatory Bowel Diseases: A Comprehensive Review

2018 ◽  
Vol 25 (28) ◽  
pp. 3374-3412 ◽  
Author(s):  
Daniela Ribeiro ◽  
Carina Proenca ◽  
Silvia Rocha ◽  
Jose L.F.C. Lima ◽  
Felix Carvalho ◽  
...  
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Intestinal Inflammation ◽  
Biological Properties ◽  
Human Diet ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Inflammatory Bowel Diseases (IBD) comprised of two disorders of idiopathic chronic intestinal inflammation that affect about three million people worldwide: Crohn’s disease and ulcerative colitis. Nowadays, the first-line of treatment for patients with mild to moderate symptoms of IBD is comprised of corticosteroids, immunosuppressants, antibiotics, and biological agents. Unfortunately, none of these drugs are curative, and their long-term use may cause severe side effects and complications. Almost 40% of IBD patients use alternative therapies to complement the conventional one, and flavonoids are gaining attention for this purpose. The biological properties of flavonoids are well documented and their antioxidant and anti-inflammatory activities have been arousing attention in the scientific community. Flavonoids are the most widely distributed polyphenols in plants and fruits, making part of the human diet. Taking into account that all ingested flavonoids are expected to exert biological actions at the gastrointestinal level, research on the modulatory effect of these compounds in IBD is of paramount importance. This review intends to summarize, in an integrated and comprehensive form, the effect of flavonoids, both in vitro and in vivo, in the different phases of the characteristic IBD inflammatory network.

Abstract 582: A Novel Adipocytokine, Omentin, Prevents Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
kyosuke kazama ◽  
Muneyoshi Okada ◽  
Hideyuki Yamawaki
Keyword(s):  
Inflammatory Responses ◽  
Ex Vivo ◽  
Negative Relationship ◽  
Weight Ratio ◽  
Vascular Wall ◽  
Structural Remodeling ◽  
Pulmonary Arterial ◽  
Hypertension Development

Background: Omentin is a novel adipocytokine mainly expressed in visceral rather than subcutaneous adipose tissue. Several epidemiological reports demonstrate the negative relationship between serum omentin level and occurrence of obesity, type 2 diabetes and hypertension. Increase of inflammatory responses, contractile reactivity and structural remodeling of vascular wall contributes to hypertension development. Our in vitro and ex vivo studies previously demonstrated that omentin prevented those hypertension-related pathological processes. In addition, our in vivo study demonstrated that intravenously injected omentin acutely inhibited agonists-induced increases of blood pressure in rats. However, the chronic effects of omentin on hypertension development are not determined. In the present study, we tested the hypothesis that chronic omentin treatment may prevent monocrotaline (MCT)-induced pulmonary arterial (PA) hypertension (PAH). Methods and Results: MCT-induced PAH was induced by a single intraperitoneal injection of MCT (60 mg/kg) to rats. Omentin (18 μg/kg/day) was intraperitoneally treated for 14 days. Chronic omentin inhibited MCT-induced increases in PA pressure (n=8-10, p<0.05). Omentin inhibited MCT-induced increases in right ventricular hypertrophy (n=6-8, p<0.01) as well as lung to body weight ratio (n=8, p<0.01). Histologically, omentin inhibited MCT-induced PA hyperplasia (n=8, p<0.01). Omentin prevented the impairment of both endothelium-dependent and-independent relaxations mediated by acetylcholine and sodium nitroprusside, respectively (n=7-13, p<0.01). Conclusion: We for the first time demonstrate that chronic omentin treatment inhibits MCT-induced PAH in rats via preventing endothelial dysfunction and/or vascular structural remodeling.

Insights on the Potential Preventive and Healing Effects of Flavonoids in Inflammatory Bowel Disease

2021 ◽  
pp. 38-66
Author(s):  
Marisa Freitas ◽  
José Miguel Pimenta Ferreira de Oliveira ◽  
M. Luísa Corvo ◽  
Félix Dias Carvalho ◽  
Eduarda Fernandes ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
In Vivo Studies ◽  
Daily Diet ◽  
Inflammatory State ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Novel Therapeutic Strategies

Inflammatory bowel disease (IBD) is characterized by sustained inflammatory processes in the gastrointestinal tract. One of the most threatening risks for IBD patients is the development of colorectal cancer, resulting from the chronic inflammatory state. Current IBD treatment presents limitations in safety and efficacy. As such, it is of paramount importance to find novel therapeutic strategies. The antioxidant and anti-inflammatory properties of flavonoids are widely recognized. Flavonoids currently found in our daily diet are likely to yield biological actions at the gastrointestinal level, suggesting a potential protective effect in IBD. However, the number of studies concerning the effects of flavonoids on intestinal inflammation is limited. This chapter intends to summarize the known effects of flavonoids in the different phases of IBD inflammatory pathways, covering all the concerning available in vivo studies.

Colonic Epithelial Surfactant Protein D Expression Correlates with Inflammation in Clinical Colonic Inflammatory Bowel Disease

2019 ◽  
Vol 25 (8) ◽  
pp. 1349-1356 ◽  
Author(s):  
Anders B Nexoe ◽  
Bartosz Pilecki ◽  
Sebastian Von Huth ◽  
Steffen Husby ◽  
Andreas A Pedersen ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Surfactant Protein ◽  
Clinical Disease ◽  
Inflammatory Activity ◽  
Surfactant Protein D ◽  
Strong Positive Correlation ◽  
Positive Correlation ◽  
Inflammatory Bowel

AbstractBackgroundInflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract. Surfactant protein D (SP-D) is expressed in the intestinal epithelium and is essential for innate host defense and regulation of inflammatory responses. Genetic variations of SP-D are associated with IBD, but the effects of SP-D in clinical disease development have not been clarified. We hypothesized that colonic epithelial SP-D expression is increased in parallel with intestinal inflammation with the capacity to dampen deleterious effects.MethodsSurgical specimens from IBD patients including Crohn’s disease (n = 9) and ulcerative colitis (n = 18) were scored for expression of SP-D and inflammatory activity. Cohoused Sftpd+/+ and Sftpd-/- mouse littermates were subjected to dextran sodium sulfate (DSS) for 7 days to induce colitis. Colonic tissue was scored for histologic damage and analyzed for inflammatory markers and expression of SP-D.ResultsSurgical specimens from IBD patients showed a strong positive correlation between immunoscore for SP-D and inflammatory activity (R2 = 0.78, P < 0.0001). In mice, colonic epithelial SP-D expression was very low, and DSS-induced colitis was unaffected by SP-D deficiency, although DSS induced transcription of colonic SP-D to a mild degree.ConclusionsA strong positive correlation between inflammatory activity and epithelial expression of SP-D was observed in surgical specimens from IBD patients supporting a role for SP-D in clinical disease. The in vivo study was inconclusive due to very low intestinal SP-D expression in the mouse. Further studies are warranted to support that increased SP-D expression in the human colonic epithelium is protective against intestinal inflammation.

Sign in / Sign up

Export Citation Format

Share Document