Molecular and cellular biology of the urokinase/urokinase receptor -related vascular remodeling: role in vascular inflammation
Cardiology, Angiology
Cell Biology
Final Report Abstract
Inflammatory role of urokinase receptor (uPAR) is well documented. However, its role in promotion of the inflammatory response was mainly attributed to the regulation of inflammatory cells migration. In this project we showed that uPAR can directly interact with TLR4 and scavenger receptor CD36 and mediates pro-inflammatory response to Pathogen Associated Molecular Pattern (PAMP) and Danger Associated Molecular Pattern (DAMP) molecules. Using several cell types, we have demonstrated that cellular signaling and release of inflammatory cytokines are both promoted by uPAR expression and interaction with scavenger receptors and confirmed functionality of those complexes in vivo. Our data offer new explanation on the role of uPAR in inflammation associated with several pathological conditions. Further research is needed to characterize in details molecular interactions of uPAR with TLR4 and its co-receptors. It will also be important to identify the nature of DAMP ligands activating the receptors complexes under specific pathological conditions. Potentially, blocking receptors interactions can be beneficial to finely regulate inflammatory response of cells. Thus, uPAR expression under normal conditions is weak and therefore blocking uPAR/TLR4 interactions should have less side effects.
Publications
- CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling. Cell Death Dis. 2016 Sep 29;7(9):e2383
Narayanaswamy PB, Tkachuk S, Haller H, Dumler I, Kiyan Y
(See online at https://doi.org/10.1038/cddis.2016.291)
