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Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis. | LitMetric

Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis.

Cell Rep

Institute for Bioinnovation, Biomedical Science Research Center (BSRC) "Alexander Fleming," Vari, Attika, Greece; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Published: May 2021

AI Article Synopsis

  • - The study focuses on the role of Tumor progression locus 2 (Tpl2) in endothelial cells, which affects vascular permeability and immune cell infiltration during inflammation and cancer progression.
  • - Deleting Tpl2 in endothelial cells decreases vascular permeability by changing the expression of claudin-5 and interfering with JNK signaling, leading to improved disease outcomes in models of autoimmune encephalomyelitis and lung cancer metastasis.
  • - The findings suggest that targeting the Tpl2 pathway in endothelial cells could be a promising therapeutic strategy for treating chronic inflammatory and metastatic conditions.

Article Abstract

Increased vascular permeability and leakage are hallmarks of several pathologies and determine disease progression and severity by facilitating inflammatory/metastatic cell infiltration. Using tissue-specific genetic ablation in endothelial cells, we have investigated in vivo the role of Tumor progression locus 2 (Tpl2), a mitogen-activated protein kinase kinase kinase (MAP3K) member with pleiotropic effects in inflammation and cancer. In response to proinflammatory stimuli, endothelial Tpl2 deletion alters tight junction claudin-5 protein expression through inhibition of JNK signaling and lysosomal degradation activation, resulting in reduced vascular permeability and immune cell infiltration. This results in significantly attenuated disease scores in experimental autoimmune encephalomyelitis and fewer tumor nodules in a hematogenic lung cancer metastasis model. Accordingly, pharmacologic inhibition of Tpl2 or small interfering RNA (siRNA)-mediated Tpl2 knockdown recapitulates our findings and reduces lung metastatic tumor invasions. These results establish an endothelial-specific role for Tpl2 and highlight the therapeutic potential of blocking the endothelial-specific Tpl2 pathway in chronic inflammatory and metastatic diseases.

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Source
http://dx.doi.org/10.1016/j.celrep.2021.109168DOI Listing

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