UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus.

Both TLR7 and NF-κB hyperactivity are known to contribute to pathogenesis in Systemic Lupus Erythematosus (SLE), driving a pro-interferon response, autoreactive B cell expansion and autoantibody production. UBE2L3 is an SLE susceptibility gene which drives plasmablast/plasma cell expansion in SLE, but its role in TLR7 signalling has not been elucidated. We aimed to investigate the role of UBE2L3 in TLR7-mediated NF-κB activation, and the effect of UBE2L3 inhibition by Dimethyl Fumarate (DMF) on SLE B cell differentiation in vitro.

Proangiogenic Growth Factor Therapy for the Treatment of Refractory Angina: A Meta-analysis.

Background: Refractory angina (RFA; limiting angina despite optimal medical therapy) is a growing, global problem, with limited treatment options. Therefore, we conducted a systematic review of randomized controlled trials (RCTs) to evaluate the effect of proangiogenic growth factor therapy (in the form of vascular growth factors delivered either as recombinant proteins or gene therapy) in patients with RFA ineligible for revascularization.

Methods: We performed a meta-analysis (PROSPERO: CRD42018107283) of RCTs as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology.

Novel application of live imaging to determine the functional cell biology of endothelial-to-mesenchymal transition (EndMT) within a liver-on-a-chip platform.

Objective: Imaging endothelial cell behaviour under physiological conditions, particularly those associated with chronic fibrotic pathologies, is an incredibly challenging endeavour. While short-term assessments (hours) can be achieved with techniques such as intravital microscopy, vascular changes often occur over days and weeks which is unfeasible with current imaging techniques. These challenges are exemplified within the liver where liver sinusoidal endothelial cells (LSECs) are known to undergo dramatic changes termed endothelial-to-mesenchymal transition (EndMT) during fibrotic liver disease.

Neutrophil breaching of the blood vessel pericyte layer during diapedesis requires mast cell-derived IL-17A.

Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots.

Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis in vitro.

Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from wild-type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs).

CD148 Deficiency in Fibroblasts Promotes the Development of Pulmonary Fibrosis.

CD148/PTRJ (receptor-like protein tyrosine phosphatase η) exerts antifibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized. We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF). Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin and then assessed for pulmonary fibrosis.

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

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Syndecan receptors: pericellular regulators in development and inflammatory disease.

The syndecans are the major family of transmembrane proteoglycans, usually bearing multiple heparan sulfate chains. They are present on virtually all nucleated cells of vertebrates and are also present in invertebrates, indicative of a long evolutionary history. Genetic models in both vertebrates and invertebrates have shown that syndecans link to the actin cytoskeleton and can fine-tune cell adhesion, migration, junction formation, polarity and differentiation.

Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2.

Mesoglycan is a drug based on a mixture of glycosaminoglycans mainly used for the treatment of blood vessel diseases acting as antithrombotic and profibrinolytic drugs. Besides the numerous clinical studies, there is no information about its function on the fibrinolytic cascade. Here, we have elucidated the mechanism of action by which mesoglycan induces the activation of plasmin from endothelial cells.

ROR2 blockade as a therapy for osteoarthritis.

Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase-like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling.

Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis.

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface.

Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling.

Objective: Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown.

Syndecan-3 in Inflammation and Angiogenesis.

Syndecans are a four member multifunctional family of cell surface molecules with diverse biological roles. Syndecan-3 (SDC3) is the largest of these, but in comparison to the other family members relatively little is known about this molecule. SDC3 null mice grow and develop normally, all be it with subtle anatomical phenotypes in the brain.

Translating the matrix.

This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders.

Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1.

Regular consumption of low-dose aspirin reduces the occurrence of colorectal, esophageal, stomach, and gastrointestinal cancers. The underlying mechanism is unknown but may be linked to inhibition of angiogenesis. Because the effective doses of aspirin are consistent with the inhibition of cyclooxygenase-1 in platelets, we used liquid chromatography with tandem mass spectrometry analyses and immunoassays of human platelet releasates coupled with angiogenesis assays to search for the mediators of these effects.

NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming.

The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts.

ICAM-1-expressing neutrophils exhibit enhanced effector functions in murine models of endotoxemia.

Intracellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein expressed on the cell surface of numerous cell types such as endothelial and epithelial cells, vascular smooth muscle cells, and certain leukocyte subsets. With respect to the latter, ICAM-1 has been detected on neutrophils in several clinical and experimental settings, but little is known about the regulation of expression or function of neutrophil ICAM-1. In this study, we report on the de novo induction of ICAM-1 on the cell surface of murine neutrophils by lipopolysaccharide (LPS), tumor necrosis factor, and zymosan particles in vitro.

Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states.

Background: Tissue infiltration by neutrophils during acute inflammatory states causes substantial tissue injury. While the magnitude of tissue neutrophil accumulation in innate immune responses is profoundly greater in males than females, fundamental aspects of the molecular mechanisms underlying these sex differences remain largely unknown.

Methods: We investigated sex differences in neutrophil stimulation and recruitment in ischemia/reperfusion (I/R; mesenteric or renal) or carrageenan pleurisy in rats or mice, as well as skin injury in human volunteers.

Sexual dimorphisms in leukocyte trafficking in a mouse peritonitis model.

Sexual dimorphisms exist in the incidence and severity of many diseases, with females demonstrating relative protection from inflammatory conditions. The extent and mechanisms by which excessive leukocyte recruitment underlies these differences are not well established, and better understanding is essential for the development of targeted therapies. Here, we set out to compare the male and female inflammatory response in a murine zymosan-induced peritonitis model and to understand how leukocyte subsets are mobilized from storage pools in both sexes.

Interleukin-6 Stimulates Defective Angiogenesis.

The cytokine IL6 has a number of tumor-promoting activities in human and experimental cancers, but its potential as an angiogenic agent has not been fully investigated. Here, we show that IL6 can directly induce vessel sprouting in the ex vivo aortic ring model, as well as endothelial cell proliferation and migration, with similar potency to VEGF. However, IL6-stimulated aortic ring vessel sprouts had defective pericyte coverage compared with VEGF-stimulated vessels.

Syndecans in angiogenesis and endothelial cell biology.

Syndecans are multifunctional heparan sulfate proteoglycans (HSPGs) with roles in cell adhesion, migration, receptor trafficking and growth-factor interactions and signalling. Studies using syndecan null animals have revealed limited roles for syndecans during development; however, under conditions of challenge or insult, several phenotypes have emerged. Angiogenesis is an important process both in development and in wound healing, but also in pathologies such as cancer and chronic inflammatory conditions.

Shed syndecan-2 inhibits angiogenesis.

Angiogenesis is essential for the development of a normal vasculature, tissue repair and reproduction, and also has roles in the progression of diseases such as cancer and rheumatoid arthritis. The heparan sulphate proteoglycan syndecan-2 is expressed on mesenchymal cells in the vasculature and, like the other members of its family, can be shed from the cell surface resulting in the release of its extracellular core protein. The purpose of this study was to establish whether shed syndecan-2 affects angiogenesis.