Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4

Prakash, Prem; Kulkarni, Paresh P.; Lentz, Steven R.; Chauhan, Anil K.

doi:10.1182/blood-2014-10-608653

Cited by 62 publications

(72 citation statements)

References 52 publications

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“…Additionally, we demonstrated direct interaction of Fn-EDA with platelet TLR4. 7 Based on these findings, we speculate that elevated Fn-EDA in the plasma of Apoe −/− mice may potentiate cerebral thrombosis through the platelet TLR4 pathway. Platelets have all the molecular machinery necessary for signal transduction downstream of TLR4, including components of the canonical NF-κB pathway, which has been shown to play a role in platelet function.…”

Section: Discussionmentioning

confidence: 68%

“…Several previous studies, including some from our own group, have shown that Fn-EDA interacts with TLR4. 5, 7, 15, 18 We hypothesized, therefore, that Fn-EDA may upregulate TLR4 signaling in Apoe −/− mice after the ischemic insult. We measured levels of phospho IKKα/β and phospho-NFκB p65, which are components of the canonical signaling pathway downstream of TLR4, in brain homogenates prepared from the infarcted and surrounding areas following tMCAO.…”

Section: Resultsmentioning

confidence: 99%

“…3–7 Fn is a dimeric, multifunctional, adhesive glycoprotein that plays an important role in several cellular processes by providing a substrate for cell adhesion and spreading. Fn has multiple isoforms generated by alternative processing of a single primary transcript at three sites: Extra Domain A (EDA), Extra Domain B (EDB), and the Type III Homologies Connecting Segment (IIICS) (Figure S1).…”

Section: Introductionmentioning

confidence: 99%

“…We have shown previously that constitutive inclusion of the EDA in Fn gene product of WT mice (C57BL6/J) promotes arterial thrombosis 6, 7 and worsens brain injury in a transient middle cerebral artery occlusion model (tMCAO). 19 Although murine stroke models have been very useful in dissecting molecular and cellular mechanisms of brain ischemia/reperfusion injury, most of this previous work has been performed using inbred strains of WT mice, which do not model the effects of pathophysiological conditions such as hypercholesterolemia, which is a risk factor for human stroke.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation

et al. 2015

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Background The fibronectin splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts in the plasma of healthy humans, but markedly elevated in patients with comorbid conditions including diabetes and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes in such conditions. We determined the role of Fn-EDA in stroke outcome in a model of hypercholesterolemia, the apolipoprotein E-deficient (Apoe−/−) mouse. Methods and Results In a transient cerebral ischemia/reperfusion injury model, Apoe−/− mice expressing Fn deficient in EDA (Fn-EDA−/−Apoe−/− mice) exhibited smaller infarcts and improved neurological outcomes at days 1 and 8 (P<0.05 vs. Apoe−/− mice). Concomitantly, intracerebral thrombosis (assessed by fibrin (ogen) deposition) and postischemic inflammation (phospho-NF-κB p65, phospho IKKα/β, IL1-β and TNFα) within lesions of Fn-EDA−/−Apoe−/− mice were markedly decreased (P<0.05 vs. Apoe−/− mice). In a FeCl3 injury-induced carotid artery thrombosis model, thrombus growth rate and the time to occlusion were prolonged in Fn-EDA−/−Apoe−/− mice (P<0.05 vs. Apoe−/− mice). Genetic ablation of TLR4 improved stroke outcome in Apoe−/− mice (P<0.05) but had no effect on stroke outcome in Fn-EDA−/−Apoe−/− mice. Bone marrow transplantation experiments revealed that non-hematopoietic cell-derived Fn-EDA exacerbates stroke through TLR4 expressed on hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA into Apoe−/− mouse 15 minutes after reperfusion significantly improved stroke outcome. Conclusions Hypercholesterolemic mice deficient in Fn-EDA exhibit reduced cerebral thrombosis and less inflammatory response after ischemia/reperfusion injury. These findings suggest that targeting Fn-EDA could be an effective therapeutic strategy in stroke associated with hypercholesterolemia.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation

et al. 2015

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“…A pro‐thrombotic role was already established for the cellular fibronectin containing extra domain A (Fn‐EDA + ) located in the extracellular matrix but it was unclear how this was mediated. Live imaging of ferric chloride‐induced injury was used to assess thrombus formation in real‐time and to image platelet aggregation to highlight the role of platelet TLR4 interaction with Fn‐EDA 54 . Carotid imaging was also used to show Nestin + stromal cells direct inflammatory cell migration in a Monocyte chemoattractant protein 1‐dependent manner 55 …”

Section: Carotid Arterymentioning

confidence: 99%

Intravital microscopy in historic and contemporary immunology

2017

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In this review, we discuss intravital microscopy of immune cells, starting from its historic origins to current applications in diverse organs. It is clear from a quantitative review of the literature that intravital microscopy is a key tool in both historic and contemporary immunological research, providing unique advances in our understanding of immune responses. We have chosen to focus this review on how intravital microscopy methodologies are used to image specific organs or systems and we present recent descriptions of fundamental immunological processes that could not have been achieved by other methods. The following target organs/systems are discussed in more detail: cremaster muscle, skin (ear and dorsal skin fold chamber), lymph node, liver, lung, mesenteric vessels, carotid artery, bone marrow, brain, spleen, foetus and lastly vessels of the knee joint.

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Human fibronectin extra domain B as a biomarker for targeted therapy in cancer

et al. 2020

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The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED-B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED-B and has shown therapeutic potential when combined with cytokines, such as IL-2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED-B targeting for the imaging and treatment of various types of cancer. ED-B-centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody-based targeted therapies.

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Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4

Abstract: Key Points Fn-EDA+ promotes arterial thrombosis. Platelet TLR4 mediates the prothrombotic effect of cellular Fn.

Cited by 62 publications

References 52 publications

Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation

Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation

Intravital microscopy in historic and contemporary immunology

Human fibronectin extra domain B as a biomarker for targeted therapy in cancer

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