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Piezo1 and G_q/G₁₁ promote endothelial inflammation depending on flow pattern and integrin activation.

ABSTRACT: The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-?B activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y₂ receptor, and G_q/G₁₁-mediated signaling. However, only disturbed flow leads to Piezo1- and G_q/G₁₁-mediated integrin activation resulting in focal adhesion kinase-dependent NF-?B activation. Mice with induced endothelium-specific deficiency of Piezo1 or G?_q/G?₁₁ show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.

SUBMITTER: Albarran-Juarez J

PROVIDER: S-EPMC6170174 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Piezo1 and G<sub>q</sub>/G<sub>11</sub> promote endothelial inflammation depending on flow pattern and integrin activation.

Albarrán-Juárez Julián J Iring Andras A Wang ShengPeng S Joseph Sayali S Grimm Myriam M Strilic Boris B Wettschureck Nina N Althoff Till F TF Offermanns Stefan S

The Journal of experimental medicine 20180907 10

The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both lamin ...[more]

PMID: 30194266

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Project description:BACKGROUND & AIMS:Hepatic recruitment of monocyte-derived macrophages (MoMFs) contributes to the inflammatory response in non-alcoholic steatohepatitis (NASH). However, how hepatocyte lipotoxicity promotes MoMF inflammation is unclear. Here we demonstrate that lipotoxic hepatocyte-derived extracellular vesicles (LPC-EVs) are enriched with active integrin ?1 (ITG?1), which promotes monocyte adhesion and liver inflammation in murine NASH. METHODS:Hepatocytes were treated with either vehicle or the toxic lipid mediator lysophosphatidylcholine (LPC); EVs were isolated from the conditioned media and subjected to proteomic analysis. C57BL/6J mice were fed a diet rich in fat, fructose, and cholesterol (FFC) to induce NASH. Mice were treated with anti-ITG?1 neutralizing antibody (ITG?1Ab) or control IgG isotype. RESULTS:Ingenuity® Pathway Analysis of the LPC-EV proteome indicated that ITG signaling is an overrepresented canonical pathway. Immunogold electron microscopy and nanoscale flow cytometry confirmed that LPC-EVs were enriched with activated ITG?1. Furthermore, we showed that LPC treatment in hepatocytes activates ITG?1 and mediates its endocytic trafficking and sorting into EVs. LPC-EVs enhanced monocyte adhesion to liver sinusoidal cells, as observed by shear stress adhesion assay. This adhesion was attenuated in the presence of ITG?1Ab. FFC-fed, ITG?1Ab-treated mice displayed reduced inflammation, defined by decreased hepatic infiltration and activation of proinflammatory MoMFs, as assessed by immunohistochemistry, mRNA expression, and flow cytometry. Likewise, mass cytometry by time-of-flight on intrahepatic leukocytes showed that ITG?1Ab reduced levels of infiltrating proinflammatory monocytes. Furthermore, ITG?1Ab treatment significantly ameliorated liver injury and fibrosis. CONCLUSIONS:Lipotoxic EVs mediate monocyte adhesion to LSECs mainly through an ITG?1-dependent mechanism. ITG?1Ab ameliorates diet-induced NASH in mice by reducing MoMF-driven inflammation, suggesting that blocking ITG?1 is a potential anti-inflammatory therapeutic strategy in human NASH. LAY SUMMARY:Herein, we report that a cell adhesion molecule termed integrin ?1 (ITG?1) plays a key role in the progression of non-alcoholic steatohepatitis (NASH). ITG?1 is released from hepatocytes under lipotoxic stress as a cargo of extracellular vesicles, and mediates monocyte adhesion to liver sinusoidal endothelial cells, which is an essential step in hepatic inflammation. In a mouse model of NASH, blocking ITG?1 reduces liver inflammation, injury and fibrosis. Hence, ITG?1 inhibition may serve as a new therapeutic strategy for NASH.

Dataset Information

Piezo1 and G_q/G₁₁ promote endothelial inflammation depending on flow pattern and integrin activation.

Publications

Piezo1 and G<sub>q</sub>/G<sub>11</sub> promote endothelial inflammation depending on flow pattern and integrin activation.

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Dataset Information

Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation.

Publications

Piezo1 and G<sub>q</sub>/G<sub>11</sub> promote endothelial inflammation depending on flow pattern and integrin activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Piezo1 and G_q/G₁₁ promote endothelial inflammation depending on flow pattern and integrin activation.