Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630

Plasticity of the endoderm

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Αρχαιολογία Καταστροφών. Ερμηνεύοντας φυσικές καταστροφές που σημάδεψαν τον αρχαίο κόσμο

Η αρχαιολογία καταστροφών αποτελεί ένα νέο σχετικά κλάδο της αρχαιολογίας, ταχέως αναπτυσσόμενο, που δημιουργήθηκε στα πλαίσια εξέλιξης της επιστήμης αυτής. Μάλιστα, φαίνεται να διαδραματίζει σημαντικό ρόλο σε επιστημονικά πεδία όπως οι ανθρωπιστικές και περιβαλλοντικές επιστήμες, στην διαχείριση κινδύνων και στις πολιτικές πρόληψης και μετριασμού κατά την διάρκεια των ιστορικών και προϊστορικών χρόνων. Φυσικές καταστροφές όπως ξηρασία, πλημμύρες, επιδημίες, ηφαιστειακές εκρήξεις, πτώση μετεωριτών, τσουνάμι και σεισμοί έπληξαν με τέτοια σφοδρότητα τον αρχαίο κόσμο που οδήγησαν στην κατάρρευση ή ακόμη και τον αφανισμό μεγάλων πολιτισμών. Στα αρχεία της αρχαιολογίας υπάρχουν άφθονες αναφορές για «στρώματα καταστροφής», που μπορεί να μαρτυρούν φυσικές καταστροφές, πολεμικές συγκρούσεις, επιδρομές λαών, πολιτικο-οικονομικές αναταράξεις κλπ. Η αρχαιολογία καταστροφών, με την σύμπραξη και άλλων επιστημονικών κλάδων, συνθέτει την εικόνα των πληγέντων αρχαίων κοινωνιών και παρέχει σημαντικές πληροφορίες για μελλοντικές καταστροφές. Ειδικότερα, η αρχαιολογία καταστροφών, αναδεικνύει τον αντίκτυπο των φυσικών καταστροφών στην εξέλιξη του ανθρώπινου πολιτισμού, εντοπίζει το είδος των φυσικών καταστροφών και την συχνότητά τους, ερευνά την διαδικασία προσαρμογής των πληγέντων κοινωνιών, εξερευνά τα «άγνωστα» τοπία που δημιουργούνται μετά από φυσικές καταστροφές και ασχολείται με ζητήματα διαχείρισης κινδύνων που αφορούν την πολιτιστική κληρονομιά στις σύγχρονες κοινωνίες. Στην παρούσα εργασία θα απαντηθούν ερωτήματα όπως: τί είναι η αρχαιολογία καταστροφών, ποια η μεθοδολογία της και θα εξεταστεί πως αυτή μπορεί να εφαρμοστεί στο πεδίο των σύγχρονων καταστροφών. Στην συνέχεια θα γίνει αναφορά στην ιστορική σεισμολογία, την περίοδο δηλαδή που ξεκινά από το 550 π.Χ., έως το 1550 μ.Χ., όπου θα αναφερθούν οι πρώτες ερμηνείες που έδωσαν οι έλληνες φιλόσοφοι σχετικά με τα αίτια γένεσης των σεισμών. Θα ακολουθήσουν τρεις μελέτες περιπτώσεων αρχαίων πολιτισμών που επλήγησαν από σεισμούς: α) Ο σεισμός του 365 μ. Χ. και το τσουνάμι που ακολούθησε πλήττοντας πολλές παράκτιες περιοχές της Ανατολικής Μεσογείου, β) το τσουνάμι του 479 π. Χ. που χτύπησε την περιοχή της Ποτίδαιας και γ) ο σεισμός του 373 π. Χ. και το τσουνάμι που εξαφάνισε την Αρχαία Ελίκη. Κοινό στοιχείο και των τριών περιπτώσεων είναι οι σεισμοί και τα συνοδά φαινόμενα που ακολούθησαν καταστρέφοντας ολόκληρες πόλεις και προκαλώντας χιλιάδες θύματα. Σχετικά με τις περιπτώσεις αυτές θα αναφερθεί το ιστορικό πλαίσιο μέσα στο οποίο χτύπησαν αυτές οι καταστροφές, θα καταγραφούν οι ιστορικές αναφορές και οι ερμηνείες που δόθηκαν για την εξήγηση των φαινομένων αυτών και θα ακολουθήσει η σύγχρονη επιστημονική εξήγηση αυτών.Disaster archeology is a relatively new, rapidly expanding field of archeology created in the context of developing this science. Indeed, it seems to play an important role concerning scientific fields such as human and environmental sciences, risk management, and prevention and mitigation policies during historic and prehistoric times. Natural disasters such as droughts, floods, epidemics, volcanic eruptions, meteor falls, tsunamis and earthquakes had so severely affected the ancient world that led to the collapse or even extinction of large civilizations. Archeology archives have abundant references to "layers of destruction", which can refer to natural disasters, war conflicts, peoples' invasions, political and economic turmoil, etc. Disaster archeology, together with other scientific fields, composes the image of ancient societies that suffered from disasters and provides important information on future disasters. More specifically, disaster archeology highlights the impact of natural disasters on the evolution of human civilization, detects the nature and frequency of natural disasters, explores the process of adaptation of societies experienced disasters, explores the "unknown" landscapes created by natural disasters, and deals with risk management issues related to cultural heritage in modern societies. In this paper, some questions will be answered such as what disaster archeology is, what its methodology is and how it can be applied in the field of modern disasters. Furthermore, historical seismology dating from 550 BC to 1550 AD will be analyzed and the first interpretations of the causes of the earthquakes by Greek philosophers will be mentioned. Three case studies of ancient civilizations affected by earthquakes will follow: a) The earthquake happened in 365 BC and the tsunami that followed affecting many coastal areas of the Eastern Mediterranean b) The tsunami happened in 479 BC that hit Potidea and c) the earthquake of 373 BC and the tsunami that destroyed Ancient Eliki. The common element of all three cases is the earthquakes and the phenomena that followed, destroying entire cities and having thousands of victims. As far as these cases are concerned, the historical context of these disasters will be mentioned, the historical references and interpretations given to explain these phenomena will be recorded while the modern scientific explanation will follow

Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection

Islet inflammation and cytokine production are implicated in pancreatic β-cell dysfunction and diabetes pathogenesis. However, we lack therapeutics to protect the insulin-producing β-cells from inflammatory damage. Closing this clinical gap requires the establishment of new disease models of islet inflammation to facilitate screening efforts aimed at identifying new protective agents. Here, we have developed a genetic model of Interleukin-1β (Il-1β)-driven islet inflammation in zebrafish, a vertebrate that allows for non-invasive imaging of β-cells and in vivo drug discovery. Live imaging of immune cells and β-cells in our model revealed dynamic migration, increased visitation and prolonged macrophage retention in the islet, together with robust activation of NF-κB signalling in β-cells. We find that Il-1β-mediated inflammation does not cause β-cell destruction but, rather, it impairs β-cell function and identity. In vivo, β-cells exhibit impaired glucose-stimulated calcium influx and reduced expression of genes involved in function and maturity. These defects are accompanied by α-cell expansion, glucose intolerance and hyperglycemia following a glucose challenge. Notably, we show that a medicinal plant derivative (wedelolactone) is capable of reducing the immune-cell infiltration while also ameliorating the hyperglycemic phenotype of our model. Importantly, these anti-diabetic properties in zebrafish are predictive of wedelolactone's efficacy in protecting rodent and human islets from cytokine-induced apoptosis. In summary, this new zebrafish model of diabetes opens a window to study the interactions between immune and β-cells in vivo, while also allowing the identification of therapeutic agents for protecting β-cells from inflammation

Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism.

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism

Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-2235 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2 + neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2 + neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention