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Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling.

ABSTRACT: We previously identified aryl hydrocarbon receptor (AHR) as a novel regulator of megakaryocytic differentiation and polyploidization and reported that AHR-null mice have approximately 15% fewer platelets than do wild-type mice, yet they exhibit a dramatic, unexplained bleeding phenotype.The current work tests our hypothesis that AHR-null platelets are functionally deficient, contributing to the previously reported (yet unexplained) bleeding phenotype present in AHR-null mice.AHR-null bone marrow was ex vivo differentiated with thrombopoietin with or without AHR ligands or AHR inhibitors and analyzed for degree of megakaryopoiesis and polyploidization. Platelet function of AHR-null mice was assessed with aggregation and spreading assays. Platelet signaling was examined using Western analysis and Rac activity assays.AHR ligands differentiate murine bone marrow-derived progenitors into polyploid megakaryocytes in the absence of thrombopoietin, and AHR inhibitors block thrombopoietin-induced megakaryocytic differentiation. Despite their responsiveness toward thrombin, AHR-null platelets demonstrate decreased aggregation and spreading in response to collagen compared with wild-type platelets. AHR-null platelets bind fibrinogen after stimulation with thrombin or AYPGKF and aggregate in response to AYPGKF and adenosine diphosphate. Mechanistically, AHR absence led to down-regulation of Vav1 and Vav3, altered phospholipase C?2 phosphorylation, decreased Rac1 activation, and reduced platelet activation in response to collagen.These results are consistent with a role for AHR in platelet function, especially as it relates to platelet aggregation and spreading in response to collagen. Our work suggests AHR is a critical component of the physiologic response that platelets undergo in response to collagen and may provide novel treatment options for patients with bleeding disorders.

SUBMITTER: Lindsey S

PROVIDER: S-EPMC4008149 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling.

Lindsey S S Jiang J J Woulfe D D Papoutsakis E T ET

Journal of thrombosis and haemostasis : JTH 20140101 3

<h4>Background</h4>We previously identified aryl hydrocarbon receptor (AHR) as a novel regulator of megakaryocytic differentiation and polyploidization and reported that AHR-null mice have approximately 15% fewer platelets than do wild-type mice, yet they exhibit a dramatic, unexplained bleeding phenotype.<h4>Objectives</h4>The current work tests our hypothesis that AHR-null platelets are functionally deficient, contributing to the previously reported (yet unexplained) bleeding phenotype present ...[more]

PMID: 24410994

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Project description:Background & aimsThe role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice.MethodsWe studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting.ResultsAhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor β-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor β-induced fibrogenesis by disrupting the interaction of Smad3 with β-catenin, which prevents the expression of genes that mediate fibrogenesis.ConclusionsIn studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.

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Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling.

Publications

Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling.

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