Impaired Resolution of Inflammation in the<i>Endoglin</i>Heterozygous Mouse Model of Chronic Colitis

Peter, Madonna; Jerkić, Mirjana; Sotov, Valentin; Douda, David N.; Ardelean, Daniela S.; Ghamami, Niousha; Lakschevitz, Flavia S.; Khan, Meraj A.; Robertson, Susan J.; Glogauer, Michael; Philpott, Dana J.; Palaniyar, Nades; Letarte, Michelle

doi:10.1155/2014/767185

Cited by 31 publications

(34 citation statements)

References 56 publications

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“…These genes were also associated with extracellular matrix (ECM) organization, collagen fibril organization and mitogen-activated protein kinase cascade. However, the upregulated genes were found to be involved in the negative regulation of endothelial cell proliferation and angiogenesis, which was in contrast to the majority of previous studies and may require further investigation (13,14).…”

Section: Differentially Expressed Genes In CD Compared With Normal Ccontrasting

confidence: 86%

Comprehensive bioinformatics analyses of Crohn's disease

Zhou

Zhan

Huang

et al. 2017

Molecular Medicine Reports

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Crohn's disease (CD) is a chronic, relapsing inflammatory disease with increasing incidence and prevalence worldwide. In previous years, the accumulation of microarray data has provided us an approach to obtain further insight into CD. In the present study, the microarray data of CD was comprehensively analyzed using multiple bioinformatics methods, and the pathobiological process of the disease was examined. Gene expression data from colon tissues of patients with CD were obtained from the Gene Expression Omnibus database; following which differentially expressed genes were identified between CD and control sample groups. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to investigate which functions and pathways in which the differentially expressed genes enriched. TargetScan and miRDB databases were then used to predict which microRNAs (miRNAs) regulated the differentially expressed genes. As a result, a total of 432 differentially expressed genes, including 229 upregulated and 203 downregulated genes, including matrix metallopeptidase 3 and glutathione S‑transferase α1, were identified in CD samples. These differentially expressed genes were significantly involved in regulation of the inflammatory response, innate immune response, cell migration, extracellular matrix organization, Janus kinase/signal transducers and activators of transcription signaling pathway, and cytokine‑cytokine receptor interaction. The miRNA-gene network showed that miR‑149‑3p and miR‑4447 regulated the most differentially expressed genes. These findings extend current understanding of the mechanisms underlying CD, and the differentially expressed genes and regulator miRNAs identified may be used as potential biomarkers and therapeutic targets for CD.

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Section: Differentially Expressed Genes In CD Compared With Normal Ccontrasting

confidence: 86%

Comprehensive bioinformatics analyses of Crohn's disease

Zhou

Zhan

Huang

et al. 2017

Molecular Medicine Reports

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“…However, their data suggest that ENG promotes leukocyte transmigration and that inflammation triggered by carrageenan and LPS leads to lower leukocyte TEM to peritoneum or lungs in Eng +/2 vs. control mice. In contrast, our recent study showed increased gut inflammation and myeloid infiltration in colitic Eng +/2 vs. control mice (28). More experiments are needed to address these differences, but it should be noted that increased incidence of severe infections has been reported in patients with HHT, which could in part be associated with increased inflammation and leukocyte TEM (29,30).…”

Section: Discussionmentioning

confidence: 73%

Increased endothelial cell permeability in endoglin-deficient cells

Jerkić¹,

Letarte²

2015

The FASEB Journal

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Endoglin (ENG) is a TGF-b superfamily coreceptor essential for vascular endothelium integrity. ENG mutations lead to a vascular dysplasia associated with frequent hemorrhages in multiple organs, whereas ENG null mouse embryos die at midgestation with impaired heart development and leaky vasculature. ENG interacts with several proteins involved in cell adhesion, and we postulated that it regulates vascular permeability. The current study assessed the permeability of ENG homozygous null (Eng 2/2 ), heterozygous (Eng +/2 ), and normal (Eng +/+ ) mouse embryonic endothelial cell (EC) lines. Permeability, measured by passage of fluorescent dextran through EC monolayers, was increased 2.9-and 1.7-fold for Eng 2/2 and Eng +/2 ECs, respectively, compared to control ECs and was not increased by TGF-b1 or VEGF. Prolonged starvation increased Eng 2/2 EC permeability by 3.7-fold with no effect on control ECs; neutrophils transmigrated faster through Eng 2/2 than Eng +/+ monolayers. Using a pull-down assay, we demonstrate that Ras homolog gene family (Rho) A is constitutively active in Eng 2/2 and EngECs. We show that the endothelial barrier destabilizing factor thrombospondin-1 and its receptor-like protein tyrosine phosphatase are increased, whereas stabilizing factors VEGF receptor 2, vascular endothelial-cadherin, p21-activated kinase, and Ras-related C3 botulinum toxin substrate 2 are decreased in Eng 2/2 cells. Our findings indicate that ENG deficiency leads to EC hyperpermeability through constitutive activation of RhoA and destabilization of endothelial barrier function.-Jerkic, M., Letarte, M. Increased endothelial cell permeability in endoglin-deficient cells. FASEB J. 29, 3678-3688 (2015). www.fasebj.org

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“…CD105 is an accessory receptor for TGFβ (97-99), CD209 is a receptor for ICAM3 that facilitates APC function (100), and CD206 is the macrophage mannose receptor that facilitates phagocytosis (101). CD105 is implicated in wounding and inflammation (102-104) , and the expression of CD209 and CD206 in CD11c hi decidual macrophages has been associated with APC function (23). Taken together, these results suggest that besides having an immunoregulatory role, M2-like macrophages in the decidua basalis may have an APC function and facilitate T-cell tolerance during late gestation.…”

Section: Discussionmentioning

confidence: 99%

An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment

Romero

Miller

et al. 2016

The Journal of Immunology

160

137

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Macrophages are implicated in the local inflammatory response that accompanies spontaneous preterm labor/birth; however, their role is poorly understood. We hypothesized that decidual macrophages undergo an M1 polarization during spontaneous preterm labor and that PPARγ activation via rosiglitazone would attenuate the macrophage-mediated inflammatory response, preventing preterm birth. Herein, we show that: 1) decidual macrophages undergo an M1-like polarization during spontaneous term and preterm labor; 2) M2-like macrophages are more abundant than M1-like macrophages in decidual tissue; 3) decidual M2-like macrophages are reduced in preterm pregnancies compared to term pregnancies, regardless of the presence of labor; 4) decidual macrophages express high levels of TNF and IL12, but low levels of PPARγ, during spontaneous preterm labor; 5) decidual macrophages from women who underwent spontaneous preterm labor display plasticity by M1↔M2 polarization in vitro; 6) incubation with rosiglitazone reduces the expression of TNF and IL12 in decidual macrophages from women who underwent spontaneous preterm labor; and 7) treatment with rosiglitazone reduces the rate of LPS-induced preterm birth and improves neonatal outcomes by reducing the systemic pro-inflammatory response in B6 mice and down-regulating mRNA and protein expression of NFκB, TNF, and IL10 in decidual and myometrial macrophages. In summary, we demonstrated that decidual M1-like macrophages are associated with spontaneous preterm labor, and that PPARγ activation via rosiglitazone can attenuate the macrophage-mediated pro-inflammatory response, preventing preterm birth and improving neonatal outcomes. These findings suggest that the PPARγ pathway is a new molecular target for future preventative strategies for spontaneous preterm labor/birth.

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Impaired Resolution of Inflammation in theEndoglinHeterozygous Mouse Model of Chronic Colitis

Cited by 31 publications

References 56 publications

Comprehensive bioinformatics analyses of Crohn's disease

Comprehensive bioinformatics analyses of Crohn's disease

Increased endothelial cell permeability in endoglin-deficient cells

An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment

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