scholarly journals IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Miao Tian ◽  
Xiumei Wang ◽  
Jihong Sun ◽  
Wenlong Lin ◽  
Lumin Chen ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Colorectal Tumorigenesis ◽  
Genetic Ablation ◽  
Prognosis Marker ◽  
Immune Sensing ◽  
Innate Immune Sensing

AbstractOccurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.

scholarly journals Molecular Basis for CCRL2 Regulation of Leukocyte Migration

2020 ◽  
Vol 8 ◽  
Author(s):  
Tiziana Schioppa ◽  
Francesca Sozio ◽  
Ilaria Barbazza ◽  
Sara Scutera ◽  
Daniela Bosisio ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Chemokine Receptors ◽  
Transmembrane Domain ◽  
Nk Cell ◽  
Structural Features ◽  
Negative Regulator ◽  
Leukocyte Migration ◽  
Genetic Ablation

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavenging functions. The only commonly recognized CCRL2 ligand is chemerin, a non-chemokine chemotactic protein. CCRL2 is expressed both by leukocytes and non-hematopoietic cells. The genetic ablation of CCRL2 has been instrumental to elucidate the role of this receptor as positive or negative regulator of inflammation. CCRL2 modulates leukocyte migration by two main mechanisms. First, when CCRL2 is expressed by barrier cells, such endothelial, and epithelial cells, it acts as a presenting molecule, contributing to the formation of a non-soluble chemotactic gradient for leukocytes expressing CMKLR1, the functional chemerin receptor. This mechanism was shown to be crucial in the induction of NK cell-dependent immune surveillance in lung cancer progression and metastasis. Second, by forming heterocomplexes with other chemokine receptors. For instance, CCRL2/CXCR2 heterodimers were shown to regulate the activation of β2-integrins in mouse neutrophils. This mini-review summarizes the current understanding of CCRL2 biology, based on experimental evidence obtained by the genetic deletion of this receptor in in vivo experimental models. Further studies are required to highlight the complex functional role of CCRL2 in different organs and pathological conditions.

scholarly journals Organoid-based models to study the role of host-microbiota interactions in IBD

2020 ◽  
Author(s):  
Martina Poletti ◽  
Kaline Arnauts ◽  
Marc Ferrante ◽  
Tamas Korcsmaros
Keyword(s):  
Gut Microbiota ◽  
Ex Vivo ◽  
Disease Onset ◽  
Intestinal Epithelial ◽  
Cell Level ◽  
Disease Mechanisms ◽  
Microbial Screening ◽  
Inflammatory Bowel ◽  
Research Questions

Abstract The gut microbiota appears to play a central role in health, and alterations in the gut microbiota are observed in both forms of Inflammatory Bowel Disease (IBD), namely Crohn’s disease and ulcerative colitis. Yet, the mechanisms behind host-microbiota interactions in IBD, especially at the intestinal epithelial cell level, are not yet fully understood. Dissecting the role of host-microbiota interactions in disease onset and progression is pivotal, and requires representative models mimicking the gastrointestinal ecosystem, including the intestinal epithelium, the gut microbiota and immune cells. New advancements in organoid microfluidics technology are facilitating the study of IBD-related microbial-epithelial crosstalk, and the discovery of novel microbial therapies. Here, we review different organoid-based ex vivo models that are currently available, and benchmark their suitability and limitations for specific research questions. Organoid applications such as patient-derived organoid biobanks for microbial screening and omics technologies are discussed, highlighting their potential to gain better mechanistic insights into disease mechanisms and eventually allowing personalized medicine.

Potential Role of the Gut Microbiome in ALS: A Systematic Review

2018 ◽  
Vol 20 (5) ◽  
pp. 513-521 ◽  
Author(s):  
Michelle L. Wright ◽  
Christina Fournier ◽  
Madelyn C. Houser ◽  
Malú Tansey ◽  
Jonathan Glass ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Potential Role ◽  
Intestinal Epithelial ◽  
Emerging Therapies ◽  
Microbiome Profile ◽  
Subsequent Publication ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) etiology and pathophysiology are not well understood. Recent data suggest that dysbiosis of gut microbiota may contribute to ALS etiology and progression. This review aims to explore evidence of associations between gut microbiota and ALS etiology and pathophysiology. Databases were searched for publications relevant to the gut microbiome in ALS. Three publications provided primary evidence of changes in microbiome profiles in ALS. An ALS mouse model revealed damaged tight junction structure and increased permeability in the intestine versus controls along with a shifted microbiome profile, including decreased levels of butyrate-producing bacteria. In a subsequent publication, again using an ALS mouse model, researchers showed that dietary supplementation with butyrate relieved symptoms and lengthened both time to onset of weight loss and survival time. In a small study of ALS patients and healthy controls, investigators also found decreased levels of butyrate-producing bacteria. Essential for maintaining gut barrier integrity, butyrate is the preferred energy source of intestinal epithelial cells. Ten other articles were reviews and commentaries providing indirect support for a role of gut microbiota in ALS pathophysiology. Thus, these studies provide a modicum of evidence implicating gut microbiota in ALS disease, although more research is needed to confirm the connection and determine pathophysiologic mechanisms. Nurses caring for these patients need to understand the gut microbiome and its potential role in ALS in order to effectively counsel patients and their families about emerging therapies (e.g., prebiotics, probiotics, and fecal microbial transplant) and their off-label uses.

scholarly journals BgTEP: an antiprotease involved in innate immune sensing in Biomphalaria glabrata

2018 ◽  
Author(s):  
Anaïs Portet ◽  
Richard Galinier ◽  
Silvain Pinaud ◽  
Julien Portela ◽  
Fanny Nowacki ◽  
...  
Keyword(s):  
Potential Role ◽  
Surface Membrane ◽  
Biomphalaria Glabrata ◽  
Freshwater Snail ◽  
Differential Expression Pattern ◽  
Immune Challenges ◽  
Immune Sensing ◽  
Innate Immune Sensing ◽  
Genomic Organisation

AbstractInsect Thioester-containing protein (iTEP) is the most recently defined group among the TEP superfamily. TEPs are key components of the immune system, and iTEPs from flies and mosquitoes were shown to be major immune weapons. Initially characterised from insects, TEP genes homologous to iTEP were further described from several other invertebrates including arthropods, cniderians and mollusks albeit with few functional characterisations. In the freshwater snail Biomphalaria glabrata, a vector of the schistosomiasis disease, the presence of a TEP protein (BgTEP) was previously described in a well-defined immune complex involving snail lectins (FREP) and schistosome parasite mucins (SmPoMuc).To investigate the potential role of BgTEP in the immune response of the snail, we first characterised its genomic organisation and its predicted protein structure. A phylogenetic analysis clustered BgTEP in a well-conserved subgroup of mollusk TEP. We then investigated the BgTEP expression profile in different snail tissues, and followed immune challenges using different kinds of intruders during infection kinetics. Results revealed that BgTEP is particularly expressed in hemocytes, the immune-specialised cells in invertebrates, and is secreted into the hemolymph. Transcriptomic results further evidenced an intruder-dependent differential expression pattern of BgTEP whilst interactome experiments showed that BgTEP is capable of binding to the surface of different microbes and parasite either in its full length form or in processed forms.Through this work, we report the first characterisation of a snail TEP. Our study also reveals that BgTEP may display an unexpected functional dual-role. In addition to its previously characterised anti-protease activity, we demonstrate that BgTEP can bind to the intruder surface membrane, which supports a likely opsonin role.

scholarly journals Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Ingrid Kazue Mizuno Watanabe ◽  
Magaiver Andrade-Silva ◽  
Orestes Foresto-Neto ◽  
Raphael José Ferreira Felizardo ◽  
Marco Aurélio Costa Matheus ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Proinflammatory Cytokines ◽  
Renal Injury ◽  
Type I Collagen ◽  
Primary Response ◽  
Type I ◽  
Intestinal Epithelial ◽  
Mesenteric Lymph Nodes ◽  
Myd88 Signaling

Increasing evidence shows the essential participation of gut microbiota in human health and diseases by shaping local and systemic immunity. Despite an accumulating body of studies showing that chronic kidney disease (CKD) is closely associated with disturbances in the composition of gut microbiota, it remains unclear the importance of gut microbiota in the onset and development of CKD. For the purpose of untangling the role of gut microbiota in CKD, gut microbiota was depleted with a pool of broad-spectrum antibiotics in mice submitted to unilateral ureteral obstruction (UUO). Depletion of gut microbiota significantly decreased levels of proinflammatory cytokines and fibrosis markers, attenuating renal injury. Additionally, to study whether the pathogenic role of gut microbiota is dependent of microbial-host crosstalk, we generated mice lacking Myd88 (myeloid differentiation primary response gene 8) expression in intestinal epithelial cells (IECs) and performed UUO. The absence of Myd88 in IECs prevented a bacterial burden in mesenteric lymph nodes as observed in WT mice after UUO and led to lower expression of proinflammatory cytokines and chemokines, reducing deposition of type I collagen and, ultimately, attenuating renal damage. Therefore, our results suggest that the presence of gut microbiota is crucial for the development of CKD and may be dependent of Myd88 signaling in IECs, which appears to be essential to maturation of immune cells intimately involved in aggravation of inflammatory scenarios.

scholarly journals Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

2016 ◽  
Vol 36 (22) ◽  
pp. 2811-2823 ◽  
Author(s):  
Shinya Imada ◽  
Yoji Murata ◽  
Takenori Kotani ◽  
Masaki Hatano ◽  
Chunxiao Sun ◽  
...  
Keyword(s):  
Target Genes ◽  
Structural Integrity ◽  
Src Family Kinases ◽  
Negative Regulator ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Cell Turnover ◽  
Epithelial Homeostasis ◽  
Mutant Phenotypes

Proper regulation of epithelial cell turnover is important for the structural integrity and homeostasis of various tissues, including the intestine. Here we show that ablation of Csk, a negative regulator of Src family kinases (SFKs), specifically in intestinal epithelial cells (IECs) resulted in the development of hyperplasia throughout the intestinal epithelium of mice. Such conditional ablation of Csk also increased the proliferative activity and turnover of IECs, disturbed the differentiation of Paneth and goblet cells, reduced the number of intestinal stem cells, and attenuated the expression of Wnt target genes in the intestine. Moreover, the tyrosine phosphorylation of focal adhesion kinase (FAK) and the activities of both Rac and Yes-associated protein (YAP) were increased in intestinal crypts or organoids of the mutant mice, whereas inhibition of Rac or YAP activity rescued the mutant phenotypes. Our results thus suggest that SFKs promote the proliferation of IECs in intestinal crypts through activation of Rac or YAP and that they thereby contribute to the proper regulation of IEC turnover and intestinal homeostasis.

scholarly journals Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis

2018 ◽  
Vol 115 (24) ◽  
pp. E5546-E5555 ◽  
Author(s):  
Ana Henriques ◽  
Vasiliki Koliaraki ◽  
George Kollias
Keyword(s):  
Mesenchymal Cells ◽  
Specific Role ◽  
Intestinal Epithelial ◽  
Invasive Potential ◽  
Genetic Ablation ◽  
Intestinal Carcinogenesis ◽  
Hsp27 Phosphorylation ◽  
Chemical Inhibition ◽  
Complete Deletion

Mesenchymal cells in the microenvironment of cancer exert important functions in tumorigenesis; however, little is known of intrinsic pathways that mediate these effects. MAPK signals, such as from MAPKAPK2 (MK2) are known to modulate tumorigenesis, yet their cell-specific role has not been determined. Here, we studied the cell-specific role of MK2 in intestinal carcinogenesis using complete and conditional ablation of MK2. We show that both genetic and chemical inhibition of MK2 led to decreased epithelial cell proliferation, associated with reduced tumor growth and invasive potential in the Apcmin/+ mouse model. Notably, this function of MK2 was not mediated by its well-described immunomodulatory role in immune cells. Deletion of MK2 in intestinal mesenchymal cells (IMCs) led to both reduced tumor multiplicity and growth. Mechanistically, MK2 in IMCs was required for Hsp27 phosphorylation and the production of downstream tumorigenic effector molecules, dominantly affecting epithelial proliferation, apoptosis, and angiogenesis. Genetic ablation of MK2 in intestinal epithelial or endothelial cells was less effective in comparison with its complete deletion, leading to reduction of tumor size via modulation of epithelial apoptosis and angiogenesis-associated proliferation, respectively. Similar results were obtained in a model of colitis-associated carcinogenesis, indicating a mesenchymal-specific role for MK2 also in this model. Our findings demonstrate the central pathogenic role of mesenchymal-specific MK2/Hsp27 axis in tumorigenesis and highlight the value of mesenchymal MK2 inhibition in the treatment of cancer.

scholarly journals Microenvironmental Metabolites in the Intestine: Messengers between Health and Disease

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 46
Author(s):  
Antonio Enrico Zaurito ◽  
Markus Tschurtschenthaler
Keyword(s):  
Communication Systems ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Intestinal Immunity ◽  
Extrinsic Factors ◽  
Colorectal Tumorigenesis ◽  
Molecular Communication Systems ◽  
Health And Disease ◽  
Inflammatory Bowel

The intestinal mucosa is a highly absorptive organ and simultaneously constitutes the physical barrier between the host and a complex outer ecosystem. Intestinal epithelial cells (IECs) represent a special node that receives signals from the host and the environment and translates them into corresponding responses. Specific molecular communication systems such as metabolites are known to transmit information across the intestinal boundary. The gut microbiota or food-derived metabolites are extrinsic factors that influence the homeostasis of the intestinal epithelium, while mitochondrial and host-derived cellular metabolites determine the identity, fitness, and regenerative capacity of IECs. Little is known, however, about the role of intrinsic and extrinsic metabolites of IECs in the initiation and progression of pathological processes such as inflammatory bowel disease and colorectal cancer as well as about their impact on intestinal immunity. In this review, we will highlight the most recent contributions on the modulatory effects of intestinal metabolites in gut pathophysiology, with a particular focus on metabolites in promoting intestinal inflammation or colorectal tumorigenesis. In addition, we will provide a perspective on the role of newly identified oncometabolites from the commensal and opportunistic microbiota in shaping response and resistance to antitumor therapy.

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