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

First Author  Nanou A Year  2021
Journal  Cell Rep Volume  35
Issue  8 Pages  109168
PubMed ID  34038728 Mgi Jnum  J:307115
Mgi Id  MGI:6717029 Doi  10.1016/j.celrep.2021.109168
Citation  Nanou A, et al. (2021) Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis. Cell Rep 35(8):109168
abstractText  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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