RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1

Skaria, Tom; Bächli, Esther; Schoedon, Gabriele

doi:10.1186/s10020-018-0048-z

Cited by 15 publications

(13 citation statements)

References 30 publications

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“…IL-1β increases endothelial permeability in many endothelial cell types. 41 The main effect appears to be due to disruption of vascular endothelial cadherin and β-catenin in the intercellular borders forming inter-endothelial gaps, which may be through induction of other factors that act on the endothelium (e.g., hypoxia inducible factor-1 or vascular endothelial growth factor-A) or the IL-1β acting directly. 42,43 Other studies have identified a synergistic role between IL-1β and R-spondin-3 in multiple endothelial cell types.…”

Section: Discussionmentioning

confidence: 99%

“…42 43 Other studies have identified a synergistic role between IL-1β and R-spondin-3 in multiple endothelial cell types. 41 While there are circumstances in which cytokine release is beneficial, such as wound healing, a detrimental effect of IL-1β in secondary cardiovascular events was demonstrated by the CANTOS trial. 12 Our results raise the possibility that selective inhibition of platelet IL-1β release, without affecting leukocyte-derived IL-1β, may be a viable target in vascular microenvironments.…”

Section: Discussionmentioning

confidence: 99%

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Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase

et al. 2021

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Objective Platelets are critical in mediating both rapid responses to injury and the development and progression of coronary disease. Several studies have shown that, after prolonged exposure to agonists, they produce and release inflammatory mediators including interleukin-1β (IL-1β), via the classical pathway (NLRP3 inflammasome and caspase-1 cleavage to release active IL-1β) as described for leukocytes. This study aimed to determine whether there is rapid release of IL-1β in response to soluble platelet agonists and whether such rapid release is NLRP3- and caspase-1-dependent. Methods and Results Using flow cytometry to detect platelet activation (and release of α and dense granule contents) and the combination of Western blotting, enzyme-linked-immunosorbent assay, and immunogold labeling transmission electron and immunofluorescence microscopy, we identified that resting human platelets contain mature IL-1β. Platelets release IL-1β within minutes in response to adenosine diphosphate (ADP), collagen, and thrombin receptor agonists, but not in response to conventional NLRP3 inflammasome agonists—lipopolysaccharide and adenosine triphosphate. The rapid release of IL-1β in response to ADP and thrombin receptor agonists was independent of caspases (including caspase-1) and NLRP3. Immature and mature IL-1β were identified as low-abundance proteins on transmission electron microscopy of human platelets, and were localized to the platelet cytosol, open canalicular system, and the periphery of α granules. Conclusion Unlike monocytes and neutrophils, human platelets are capable of rapid agonist- and time-dependent release of IL-1β by a mechanism which is independent of caspase-1 and NLRP3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase

et al. 2021

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“…IL-1β can also induce vascular permeability indirectly through induction of pro-permeability factor R-spondin 3 (RSPO3) (121). Combined treatment of IL-1β and RSPO3 can synergistically increase permeability in human coronary artery endothelial cells (HCAEC), HPAEC, human cerebral microvascular endothelial cells (HCMVEC), human brain microvascular endothelial cells (HBMVEC), and HMVECd (122).…”

Section: Il-1 Is a Potent Inducer Of Vascular Permeabilitymentioning

confidence: 99%

IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis

2019

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The IL-1 family of cytokines are well-known for their primary role in initiating inflammatory responses both in response to and acting as danger signals. It has long been established that IL-1 is capable of simultaneously regulating inflammation and angiogenesis, indeed one of IL-1's earliest names was haemopoeitn-1 due to its pro-angiogenic effects. Other IL-1 family cytokines are also known to have roles in mediating angiogenesis, either directly or indirectly via induction of proangiogenic factors such as VEGF. Of note, some of these family members appear to have directly opposing effects in different tissues and pathologies. Here we will review what is known about how the various IL-1 family members regulate vascular permeability and angiogenic function in a range of different tissues, and describe some of the mechanisms employed to achieve these effects.

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“…1A ). In addition, according to previous studies, It is known that IL-1β can activate vascular endothelial cells and induce their secretion of adhesion factors such as ICAM-1, in order to recruit inflammatory cells and trigger the inflammatory reaction of arterial walls, thus forming aneurysm ( 32 ). In the present study, HUVECs were used as an in vitro model system, and the IL-1β were used to stimulate HUVECs to simulate the inflammatory state of CA.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‑124‑5p delays the progression of cerebral aneurysm by regulating FoxO1

et al. 2021

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Cerebral aneurysm (CA) is a common brain disease, and the development of cerebral aneurysm is driven by inflammation and hemodynamic stress. MicroRNA (miR)-124-5p is reported to be associated with inflammatory response in brain disease such as cerebral ischemia-reperfusion injury. However, the function and molecular mechanism of miR-124-5p in CA are not clear, thus, the effects of miR-124-5p on inflammatory response in CA were explored. Firstly, the expression of miR-124-5p in the peripheral blood of patients with CA and the control group was detected by reverse transcription-quantitative PCR. Then, the human umbilical vein endothelial cells (HUVECs) were used as an in vitro model system and stimulated with interleukin (IL)-1β to simulate the inflammatory environment of CA, and the expression of miR-124-5p was detected. Next, the effect of miR-124-5p on the migration and invasion of HUVECs was detected using Transwell assays. Meanwhile, the function of miR-124-5p on various inflammatory factors was determined by western blotting and enzyme-linked immunosorbent assay (ELISA). Next, the TargetScan website was used to predict FoxO1 as a target gene of miR-124-5p, and this target association was validated by double luciferase reporter assay and western blotting. Finally, the interaction of miR-124-5p with FoxO1 in CA was measured by Transwell western blotting and ELISA assays. The results showed that the expression level of miR-124-5p in the peripheral blood of patients with CA was lower compared with that of control group, and the miR-124-5p in HUVECs stimulated by IL-1β was less compared with that in normal HUVECs. Besides, miR-124-5p could inhibit the migration and invasion abilities of HUVECs and the release of inflammatory factors. Additionally, the overexpression of miR-124-5p was able to inhibit the expression of FoxO1. miR-124-5p-inhibitor promoted the migration and invasion of HUVECs, as well as inflammatory response, which was weakened following the introduction of FoxO1 small interfering RNA. Overall, the present study demonstrated that miR-124-5p could prevent the occurrence and development of cerebral aneurysm by downregulating the expression of FoxO1.

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RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1

Cited by 15 publications

References 30 publications

Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase

Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase

IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis

MicroRNA‑124‑5p delays the progression of cerebral aneurysm by regulating FoxO1

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