scholarly journals TDAG8 (GPR65) Inhibits Intestinal Inflammation in the DSS-Induced Experimental Colitis Mouse Model

2018 ◽  
Author(s):  
Edward J Sanderlin ◽  
Swati Satturwar ◽  
Heng Hong ◽  
Kvin Lertpiriyapong ◽  
Mona Marie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Experimental Colitis ◽  
Therapeutic Effects ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Tissue Samples ◽  
Inflammatory Phenotypes

T cell death-associated gene 8 (TDAG8, also known as GPR65) is a proton-sensing G protein-coupled receptor (GPCR) predominantly expressed in immune cells. Genome-wide association studies identify TDAG8 as a susceptibility candidate gene linked to several human inflammatory diseases including inflammatory bowel disease (IBD), asthma, spondyloarthritis, and multiple sclerosis. In this study, our results demonstrate that mice deficient of TDAG8 exhibited more severe inflammatory phenotypes than wild-type mice in a chronic dextran sulfate sodium (DSS)-induced colitis mouse model. Several disease parameters, such as diarrhea, colon shortening, fibrosis, histopathological score, and mesenteric lymph node enlargement were aggravated in TDAG8-null mice in comparison to wild-type mice treated with DSS. Increased leukocyte infiltration and myofibroblast expansion were observed in colonic tissues of DSS-treated TDAG8-null mice. These changes may represent a cellular basis of the observed exacerbation of intestinal inflammation and fibrosis in these mice. In line with high expression of TDAG8 in infiltrated leukocytes, real-time RT-PCR revealed that TDAG8 mRNA expression was increased in inflamed intestinal tissue samples of IBD patients when compared to normal intestinal tissues. Altogether, our data demonstrate that TDAG8 suppresses intestinal inflammation and fibrosis in the chronic DSS-induced colitis mouse model, suggesting potentiation of TDAG8 with agonists may have anti-inflammatory therapeutic effects in IBD.

scholarly journals Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sean P. Kessler ◽  
Dana R. Obery ◽  
Carol de la Motte
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Hyaluronan Synthase ◽  
Wild Type ◽  
Colon Tissue ◽  
Dss Colitis ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals The Capsule Encoding the viaB Locus Reduces Interleukin-17 Expression and Mucosal Innate Responses in the Bovine Intestinal Mucosa during Infection with Salmonella enterica Serotype Typhi

2007 ◽  
Vol 75 (9) ◽  
pp. 4342-4350 ◽  
Author(s):  
Manuela Raffatellu ◽  
Renato L. Santos ◽  
Daniela Chessa ◽  
R. Paul Wilson ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Mouse Model ◽  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Fluid Secretion ◽  
Interleukin 17 ◽  
Loop Model ◽  
Wild Type ◽  
Ileal Loop ◽  
Chemokine Production

ABSTRACT The viaB locus contains genes for the biosynthesis and export of the Vi capsular antigen of Salmonella enterica serotype Typhi. Wild-type serotype Typhi induces less CXC chemokine production in tissue culture models than does an isogenic viaB mutant. Here we investigated the in vivo relevance of these observations by determining whether the presence of the viaB region prevents inflammation in two animal models of gastroenteritis. Unlike S. enterica serotype Typhimurium, serotype Typhi or a serotype Typhi viaB mutant did not elicit marked inflammatory changes in the streptomycin-pretreated mouse model. In contrast, infection of bovine ligated ileal loops with a serotype Typhi viaB mutant resulted in more fluid accumulation and higher expression of the chemokine growth-related oncogene alpha (GROα) and interleukin-17 (IL-17) than did infection with the serotype Typhi wild type. There was a marked upregulation of IL-17 expression in both the bovine ligated ileal loop model and the streptomycin-pretreated mouse model, suggesting that this cytokine is an important component of the inflammatory response to infection with Salmonella serotypes. Introduction of the cloned viaB region into serotype Typhimurium resulted in a significant reduction of GROα and IL-17 expression and in reduced fluid secretion. Our data support the idea that the viaB region plays a role in reducing intestinal inflammation in vivo.

scholarly journals Identification of Novel Genome-Wide Associations for Oral Inflammatory Traits

2020 ◽  
Author(s):  
Yanjiao Jin ◽  
Jie Yang ◽  
Shuyue Zhang ◽  
Jin Li ◽  
Songlin Wang
Keyword(s):  
Candidate Genes ◽  
Immune Regulation ◽  
Functional Annotation ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Protein Protein Interaction ◽  
Genome Wide ◽  
Causal Variants

Abstract Background: Oral diseases impact the majority of the world’s population. The following traits are common in oral inflammatory diseases: mouth ulcers, painful gums, bleeding gums, loose teeth, and toothache. Despite the prevalence of genome-wide association studies, the associations between these traits and common genomic variants, and whether pleiotropic loci are shared by some of these traits remain poorly understood. Methods: In this work, we conducted multi-trait joint analyses based on the summary statistics of genome-wide association studies of these five oral inflammatory traits from the UK Biobank, each of which is comprised of over 10,000 cases and over 300,000 controls. We estimated the genetic correlations between the five traits. We conducted fine-mapping and functional annotation based on multi-omics data to better understand the biological functions of the potential causal variants at each locus. To identify the pathways in which the candidate genes were mainly involved, we applied gene-set enrichment analysis, and further performed protein-protein interaction (PPI) analyses.Results: We identified 39 association signals that surpassed genome-wide significance, including three that were shared between two or more oral inflammatory traits, consistent with a strong correlation. Among these genome-wide significant loci, two were novel for both painful gums and toothache. We performed fine-mapping and identified causal variants at each novel locus. Further functional annotation based on multi-omics data suggested IL10 and IL12A/TRIM59 as potential candidate genes at the novel pleiotropic loci, respectively. Subsequent analyses of pathway enrichment and protein-protein interaction networks suggested the involvement of candidate genes at genome-wide significant loci in immune regulation.Conclusions: Our results highlighted the importance of immune regulation in the pathogenesis of oral inflammatory diseases. Some common immune-related pleiotropic loci or genetic variants are shared by multiple oral inflammatory traits. These findings will be beneficial for risk prediction, prevention, and therapy of oral inflammatory diseases.

Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rate

Blood ◽  
2021 ◽  
Author(s):  
Gaia Zirka ◽  
Philippe Robert ◽  
Julia Tilburg ◽  
Victoria Tishkova ◽  
Chrissta X Maracle ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Shear Rates ◽  
Extracellular Traps ◽  
Genome Wide ◽  
Healthy Donors ◽  
Von Willebrand ◽  
Willebrand Factor

Genome wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF). To explain the link between Slc44a2 and VT we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100s-1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils are preactivated with lipopolysaccharide (LPS). Moreover, specific shear conditions with high neutrophil concentration could act as a "second hit", inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. Neutrophils expressing Slc44a2/HNA-3b not being associated with these observations, these results could thus explain the association between HNA-3b and a reduced risk for VT in humans.

Abstract 15673: CRISPR-Cas9 Gene Editing in Mice Reveals Novel Thrombotic Function of a Human SNP in STXBP5

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Qiuyu Zhu ◽  
Kyung Ae Ko ◽  
Sara Ture ◽  
Craig N Morrell ◽  
Joseph M Miano ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gene Editing ◽  
Association Studies ◽  
Blood Stream ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Human Endothelial Cells ◽  
Mesenteric Vessel ◽  
Prolonged Bleeding Time ◽  
Bleeding Score

Introduction: Endothelial cells responds to vascular injury by exocytosis, releasing von Willebrand factor (vWF) into the blood stream. However, the regulation of endothelial vWF release remains poorly understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels. One top nonsynonymous single nucleotide polymorphism (SNP), rs1039084 (hg19 chr6:g.147635413A>G), encodes p. Asn436Ser substitution (STXBP5-N436S), and is associated with lower plasma vWF, higher bleeding score, and decreased venous thrombosis in humans. We recently discovered that STXBP5 inhibits endothelial vWF exocytosis and regulates thrombosis. However, the role of the STXBP5 genetic variants linked to vWF levels are not completely understood. Hypothesis: We hypothesized that STXBP5-N436S further inhibits endothelial exocytosis than wild type (STXBP5-WT). Methods: We overexpressed STXBP5-WT and STXBP5-N436S in cultured human endothelial cells and measured VWF release changes. Using CRISPR-Cas9 technique, we generated mice carrying the human rs1039084 SNP in Stxbp5 locus (Stxbp5-N437S mice). We conducted phenotypic analyses including endothelial exocytosis, hemostasis, and thrombosis in wild-type and Stxbp5-N437S mice. Results: In human endothelial cells, overexpression of STXBP5-N436S inhibits vWF exocytosis more potently than STXBP5-WT. Germline CRISPR-Cas9 gene editing efficiently and precisely knocked-in the human rs1039084 SNP in murine Stxbp5 locus, without causing detectable off-target genome cleavage. The baseline plasma vWF levels of Stxbp5-N437S mice are similar to WT mice, but Stxbp5-N437S mice showed impaired vWF exocytosis in response to epinephrine challenge. Moreover, Stxbp5-N437S mice have severe hemostasis defects displayed as prolonged bleeding time. Finally, Stxbp5-N437S mice have impaired mesenteric vessel thrombosis and carotid artery thrombosis. We are now studying the effects of the SNP upon STXBP5 structure and function. Conclusions: Our study validates the functional relevance of a candidate SNP identified by GWAS, and suggests that genetic variations within STXBP5 is a risk factor for thromboembolic disease.

scholarly journals Smad7 and Colorectal Carcinogenesis: A Double-Edged Sword

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 612 ◽  
Author(s):  
Edoardo Troncone ◽  
Giovanni Monteleone
Keyword(s):  
Immune Cells ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Association Studies ◽  
Cell Subset ◽  
Colorectal Carcinogenesis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chronic Intestinal Inflammation

Colorectal carcinogenesis is a complex process in which many immune and non-immune cells and a huge number of mediators are involved. Among these latter factors, Smad7, an inhibitor of the transforming growth factor (TGF)-β1 signaling that has been involved in the amplification of the inflammatory process sustaining chronic intestinal inflammation, is supposed to make a valid contribution to the growth and survival of colorectal cancer (CRC) cells. Smad7 is over-expressed by tumoral cells in both sporadic CRC and colitis-associated CRC, where it sustains neoplastic processes through activation of either TGFβ-dependent or non-dependent pathways. Consistently, genome-wide association studies have identified single nucleotide polymorphisms of the Smad7 gene associated with CRC and shown that either amplification or deletion of the Smad7 gene associates with a poor prognosis or better outcome, respectively. On the other hand, there is evidence that over-expression of Smad7 in immune cells infiltrating the inflamed gut of patients with inflammatory bowel disease can elicit anti-tumor responses, with the down-stream effect of attenuating CRC cell growth. Taken together, these observations suggest a double role of Smad7 in colorectal carcinogenesis, which probably depends on the cell subset and the biological context analyzed. In this review, we summarize the available evidences about the role of Smad7 in both sporadic and colitis-associated CRC.

Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn’s-Like Colitis

2020 ◽  
Author(s):  
Yi Yin ◽  
Jingjing Yang ◽  
Yongchun Pan ◽  
Zhen Guo ◽  
Yanfeng Gao ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery System ◽  
Delivery System ◽  
Lymphatic System ◽  
Intestinal Inflammation ◽  
Lymphatic Vessels ◽  
Experimental Colitis ◽  
Therapeutic Effects ◽  
Sustained Drug Release

Abstract Background and Aims Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn’s disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn’s colitis. Methods We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10−/− spontaneous experimental colitis. Results ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN. Conclusion Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.

scholarly journals Lactobacillus paracaseiReduces Intestinal Inflammation in Adoptive Transfer Mouse Model of Experimental Colitis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Manuel Oliveira ◽  
Nabil Bosco ◽  
Genevieve Perruisseau ◽  
Jeanne Nicolas ◽  
Iris Segura-Roggero ◽  
...  
Keyword(s):  
Mouse Model ◽  
Adoptive Transfer ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Lactobacillus Paracasei ◽  
Therapeutic Benefits

Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease.In vitroevidence suggested thatLactobacillus paracaseialso called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptomsin vivoIn this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2-/-recipient mice were fed with ST11 (109CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such asLactobacillus paracaseiharbor worthwhilein vivoimmunomodulatory properties to prevent intestinal inflammation by nutritional approaches.

scholarly journals Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease

2019 ◽  
Vol 28 (19) ◽  
pp. 3244-3254 ◽  
Author(s):  
Sarah Jinn ◽  
Cornelis Blauwendraat ◽  
Dawn Toolan ◽  
Cheryl A Gretzula ◽  
Robert E Drolet ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Therapeutic Strategy ◽  
Association Studies ◽  
Causal Variant ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Lysosomal Ph ◽  
Genome Wide ◽  
Attractive Candidate ◽  
Lysosomal Gene

Abstract Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.

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