Endothelial Tpl2 Regulates Vascular Barrier Function Via Tight Junction Protein Claudin-5 Promoting CNS Cell Infiltration and Tumor Metastasis

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 Tpl2, a MAP3 kinase with pleiotropic effects in inflammation and cancer. In response to pro-inflammatory stimuli, endothelial Tpl2 deletion alters Tight Junction (TJ) claudin-5 protein expression and attenuates the increase in vascular permeability, inflammatory cell infiltration and accumulation of plasma proteins. This results in significantly attenuated disease scores in Experimental Autoimmune Encephalomyelitis and significantly less tumor nodules in a haematogenic lung cancer metastasis model. Accordingly, pharmacologic inhibition of Tpl2 or siRNA-mediated Tpl2 knockdown recapitulates our findings and reduces lung metastatic tumor invasions. These results establish a novel endothelial-specific role for Tpl2 in the regulation of TJ-mediated endothelial permeability and highlight the therapeutic potential of Tpl2 blockade in chronic inflammatory and metastatic diseases.