Postdoctoral researcher Katerina Nanou from George Kollias lab published in Cell Reports a novel function for the Tpl2 kinase in the regulation of vascular permeability in neuroinflammation and cancer.
Postdoctoral researcher Katerina Nanou from George Kollias lab published in Cell Reports a novel function for the Tpl2 kinase in the regulation of vascular permeability in neuroinflammation and cancer.
Increased vascular permeability and leakage are hallmarks of several pathologies, as they facilitate inflammatory and/or metastatic cell infiltration. A new study published in Cell Reports by the Kollias lab identified that endothelial Tpl2 kinase regulates vascular permeability in neuroinflammation and cancer through JNK-mediated lysosomal degradation of Tight Junction protein claudin-5. Although the pro-inflammatory role of Tpl2 has been widely studied in immune cells, this study shows a novel endothelial-specific role for Tpl2 and highlights its significance in targeting vascular permeability for therapeutic modulation.
Endothelial cells form the Blood-Brain Barrier and they control the influx of molecules and cells within the Central Nervous System (CNS) through the Tight Junctions (TJ), specialized structures formed between adjacent endothelial cells. During Multiple Sclerosis, an autoimmune demyelinating disease, there is increased influx of immune cells, which in turn induces neurodegeneration. Using mouse models of the disease, the study showed that Tpl2 decreases the expression of TJ proteins through the JNK-mediated activation of lysosomal degradation pathway. This increased degradation of TJ proteins increases the vascular permeability allowing more immune cells within the CNS.
The study by Katerina Nanou in the Kollias lab, titled “Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis”, showed that this phenomenon was not restricted in the CNS, but similar results were seen in a lung metastatic mouse model, where the endothelium is heavily involved in cancer cell lung infiltration. Endothelial-specific Tpl2 ablation, either genetically or pharmacologically, led to reduced metastatic nodules, decreased number of inflammatory cells and increased expression of TJ proteins.
These results introduce a novel endothelial-specific role for Tpl2 and suggest the therapeutic potential of blocking the endothelial-specific Tpl2 pathway in chronic inflammatory and metastatic diseases.
Nanou A, Bourbouli M, Vetrano S, Schaeper U, Ley S, Kollias G. 2021, "Endothelial Tpl2 regulates vascular barrier function via JNK-mediated degradation of claudin-5 promoting neuroinflammation or tumor metastasis", Cell Rep., 35(8):109168. doi: 10.1016/j.celrep.2021.109168. [PubMed].