Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or 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 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. [Display omitted] •Endothelial-specific function of Tpl2 linked to vascular barrier permeability•Endothelial cell (EC)-specific Tpl2 ablation reduces neuroinflammation in EAE•Endothelial Tpl2 ablation reduces tumor nodule formation in lung metastasis model•Mechanistically, EC Tpl2 induces JNK-mediated lysosomal degradation of claudin-5 Increased vascular permeability and leakage facilitate metastatic and immune cell infiltration in inflammation. Nanou et al. show that endothelial-specific Tpl2 regulates vascular barrier permeability through JNK-mediated lysosomal degradation of tight junction protein claudin-5. Genetic or pharmacologic Tpl2 ablation in mice reduces neuroinflammation and cancer cell metastasis, highlighting its therapeutic potential.