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

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

doi:10.1182/blood-2014-10-608653

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

Journal article

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

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

Blood, Vol.125(20), pp.3164-3172

05/14/2015

DOI: 10.1182/blood-2014-10-608653

PMCID: PMC4432011

PMID: 25700433

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Abstract

Cellular fibronectin containing extra domain A (Fn-EDA+), which is produced in response to tissue injury in several disease states, has prothrombotic activity and is known to interact with Toll-like-receptor 4 (TLR4). The underlying mechanism and cell types involved in mediating the prothrombotic effect of Fn-EDA+ still remain unknown. Using intravital microscopy, we evaluated susceptibility to carotid artery thrombosis after FeCl3-induced injury in mice expressing Fn lacking EDA (Fn-EDA(-/-) mice) or Fn containing EDA (Fn-EDA(+/+) mice). Fn-EDA(-/-) mice exhibited prolonged times to first thrombus formation and complete occlusion and a significant decrease in the rate of thrombus growth (P < .05 vs Fn-EDA(+/+) mice). Genetic deletion of TLR4 reversed the accelerated thrombosis in Fn-EDA(+/+) mice (P < .05) but had no effect in Fn-EDA(-/-) mice. Bone marrow transplantation experiments revealed that TLR4 expressed on hematopoietic cells contributes to accelerated thrombosis in Fn-EDA(+/+) mice. In vitro studies showed that cellular Fn-EDA+ interacts with platelet TLR4 and promotes agonist-induced platelet aggregation. Finally, Fn-EDA(+/+) mice specifically lacking platelet TLR4 exhibited prolonged times to first thrombus formation and complete occlusion (P < .05 vs Fn-EDA(+/+) mice containing platelet TLR4). We conclude that platelet TLR4 contributes to the prothrombotic effect of cellular Fn-EDA+, suggesting another link between thrombosis and innate immunity.

Carotid Artery, Common - metabolism

Thrombosis - immunology

Male

Immunity, Innate

Toll-Like Receptor 4 - metabolism

Fibronectins - metabolism

Mice, Knockout

Platelet Aggregation

Thrombosis - metabolism

Animals

Blood Platelets - metabolism

Carotid Artery, Common - pathology

Female

Thrombosis - genetics

Fibronectins - genetics

Mice

Disease Models, Animal

Details

Title: Subtitle: Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4
Creators: Prem Prakash - Department of Internal Medicine, University of Iowa, Iowa City, IA
Paresh P Kulkarni - Department of Internal Medicine, University of Iowa, Iowa City, IA
Steven R Lentz - Department of Internal Medicine, University of Iowa, Iowa City, IA
Anil K Chauhan - Department of Internal Medicine, University of Iowa, Iowa City, IA
Resource Type: Journal article
Publication Details: Blood, Vol.125(20), pp.3164-3172
DOI: 10.1182/blood-2014-10-608653
PMID: 25700433
PMCID: PMC4432011
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: R01 HL118742 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R01 HL118246 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS
Language: English
Date published: 05/14/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094212302771

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