Τίτλος:
Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021 The Author(s)
Συγγραφείς:
Nanou, A.
Bourbouli, M.
Vetrano, S.
Schaeper, U.
Ley, S.
Kollias, G.
Λέξεις-κλειδιά:
claudin 5; mitogen activated protein kinase kinase kinase; small interfering RNA; stress activated protein kinase; tumor progression locus 2; unclassified drug; claudin 5; MAP3K8 protein, human; mitogen activated protein kinase kinase kinase; oncoprotein, adult; animal cell; animal experiment; animal model; animal tissue; Article; blood vessel permeability; cell infiltration; controlled study; endothelium cell; enzyme inhibition; experimental autoimmune encephalomyelitis; female; gene deletion; gene knockdown; human; human tissue; immunocompetent cell; in vivo study; infant; JNK signaling; lung cancer; lysosome; male; metastasis; mouse; multiple sclerosis; nervous system inflammation; nonhuman; pathogenesis; pleiotropy; protein degradation; protein expression; tight junction; tumor invasion; animal; endothelium cell; genetics; inflammation; metabolism; metastasis, Animals; Claudin-5; Endothelial Cells; Humans; Inflammation; MAP Kinase Kinase Kinases; Mice; Neoplasm Metastasis; Proto-Oncogene Proteins
DOI:
10.1016/j.celrep.2021.109168
